Learning Objectives. Case 1. Case Presentations. Interpretation of Liver Tests. Interpretation of Liver Tests. Presenter Disclosure Information

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1 Presenter Disclosure Information 11:05 11:45am Interpretation of Liver Tests SPEAKER Steven-Huy Han, MD, AGAF, FAASLD The following relationships exist related to this presentation: Steven-Huy Han, MD, AGAF, FAASLD: No financial relationships to disclose. Off-Label/Investigational Discussion In accordance with pmicme policy, faculty have been asked to disclose discussion of unlabeled or unapproved use(s) of drugs or devices during the course of their presentations. Learning Objectives Interpretation of Liver Tests Steven Han, M.D. Professor of Medicine & Surgery UCLA School of Medicine Recognize liver test patterns in various types of liver disorders Distinguish tests of liver function from tests of liver Discuss supplemental liver tests to order for specific diagnoses Case Presentations Liver Diseases ID: 30 year old Taiwanese male Ph.D. student is referred for abnormal liver tests. HPI: He recalls no prior history or knowledge of liver disease. Last month, after donating blood at the university blood drive, he was notified that his blood had been rejected. He was then advised to see his physician, at which time, he presented to the Student Health Clinic. An initial hepatic panel revealed elevated aminotransferase levels (ALT 95, AST 70).

2 Serologic tests were obtained, and he was referred to see a hepatologist. As far as history of liver disease, he recalls an episode of childhood jaundice lasting a few weeks and resolving without sequelae. He does not describe symptoms of ascites, ankle swelling, GI bleeding, or hepatic encephalopathy. His appetite is normal, and he has not noticed any change in weight or loss of muscle mass. PMH: Tonsillectomy as a child. Otherwise, unremarkable. Meds: Tylenol for headaches. (He notes increased use recently during final exams). SH: He is married. He was born in Taiwan and came to the U.S. 3 years ago to study. He is a Ph.D. in mathematics. He enjoys an occasional beer at dinnertime. No tobacco use. No IVDA. No remote blood transfusions. He had acupuncture in Taiwan. FH: PE: His father has hypertension. His mother has diabetes. Two siblings are healthy in Taiwan. A maternal uncle reportedly died of liver cancer. He has no children. Vital signs are normal. WD/WN male in NAD. SKIN: Clear without spider telangiectasia. HEENT: Normal LUNGS: Clear bilaterally. HEART: RRR without murmur. ABD: Soft, nontender, active BS. No HSM. No superficial collaterals or umbilical hernia. EXT: No clubbing or edema. No palmar erythema. Labs: - WBC 4.8, hematocrit 46.8, platelets Albumin 4.2, ALT 95, AST 70, alkaline phos. 80, total bilirubin Prothrombin time (INR) 1.0. What tests do you want next? Serologies for viral hepatitis were ordered and revealed: - Anti-HAV IgG positive. - HBsAg positive, HBc Ab IgG positive, HBs Ab negative. - Anti-HCV (ELISA) negative. What do these tests tell you? What tests do you want to order next? Hepatitis B replicative markers were ordered and revealed: - HBV DNA was 4+ positive. - HBe Ag was positive, HBe Ab was negative. Do you want to treat this patient and with what? If so, do you want any other tests first?

3 A serum alpha-fetoprotein was ordered and returned at 2500! This prompted an abdominal ultrasound, which revealed the presence of a 1.5 cm hyperechoic lesion in the anterior right hepatic lobe. A subsequent abdominal CT scan confirmed this to be a hypervascular mass suspicious for HCC. A guided biopsy demonstrated well-differentiated HCC, and a biopsy of the adjacent hepatic parenchyma revealed no cirrhosis. What do you want to do next? The patient was started on tenofovir 300 mg/d orally to suppress viral replication. He was then referred to a liver surgeon and eventually underwent a partial hepatic resection of the tumor. The surgical margins were negative. Adjacent lymph nodes were negative. Histologic examination of the resected specimen revealed no evidence of vascular invasion by the tumor. Thus far, he continues to do well in follow-up. ID: HPI: 56 year old Caucasian woman referred for abnormal liver tests. This patient first presented to her primary internist for a routine examination a few months ago when she was noted to have an elevated cholesterol (>300). Accordingly, she was started on an antihypercholesterolemic medication. A few weeks later, she represented to her internist with progressive itching, unrelieved by moisturizers. Additionally, she had noted some darkening of her urine. A biochemical liver profile was obtained revealing an increase in total bilirubin (3.5 mg/dl) and alkaline phosphatase (356 IU). Accordingly, the internist stopped the anti-hyper-cholesterolemic medication and obtained an abdominal ultrasound, which showed no evidence of extrahepatic biliary obstruction. Four weeks later in follow-up, the patient described slightly improved but persisting itch, especially after showers. Her urine also remained somewhat dark. Repeat liver tests revealed persisting bilirubin and alkaline phosphatase elevations. Accordingly, the patient was referred to a hepatologist. PMH: Diabetes mellitus, osteoporosis, arthritis and stiffness of her hands (especially during the cold season), and bad heartburn with frequent dry throat. Meds: Insulin, multivitamin supplements, calcium, and PRN motrin. SH: FH: PE: She is married and was born in New York. No significant alcohol, tobacco, or drug use history. No prior blood transfusions. She recalls an aunt who had a liver transplant, but cannot recall for what reason. Vital signs are normal. WD/WN female in NAD. SKIN: Questionably jaundice without vascular spiders. HEENT: Mild scleral icterus. Petechial lesions on her lips.

4 LUNGS: Clear bilaterally. HEART: RRR without a murmur. ABD: Soft and nontender. No flank/shifting dullness. No appreciable HSM. EXT: No clubbing. 2+ pitting edema. Tight skin on her fingers. Digital telangiectasia noted. Shiny fingernails. What are the pertinent findings in the history and physical? Labs: - WBC 4.3, hematocrit 37%, platelets Albumin 3.2, ALT 35, AST 32, alkaline phosphatase 430, total bilirubin 4.5, total protein Prothrombin time (INR) 1.7. What tests do you want to order next? What is the CREST syndrome and it s relevance here? Viral hepatitis serologies were ordered revealing: - Anti-HAV IgG negative. - HBsAg negative, HBcAb IgG positive, HBsAb positive. - Anti-HCV (ELISA) negative. Other serologic markers of autoimmune disease were ordered revealing: - ANA and SMA negative. - AMA 1:1280. What do these tests mean? Do you want to order any other tests? What do these tests suggest? What is the next management step? A liver biopsy was performed revealing a paucity of bile ducts and bridging portal-to-portal fibrosis. No steatosis was noted. No granulomas were noted. What does this mean? The patient was eventually referred for orthotopic liver transplantation (OLT), which is considered curative for Primary Biliary Cirrhosis. The patient was started on ursodeoxycholic acid 250 mg bid orally. Calcium supplements were continued and vitamin D added. Bone densitometry revealed osteopenia of the vertebral column and hips. Despite therapy, the patient noted progressive fatigue and persisting bothersome pruritis. What should be done now?

5 ID: 65 year old Caucasian gentleman presents with abnormal liver tests. HPI: This patient has no history or knowledge of liver disease. During a recent trip to Las Vegas, he began to notice swelling of his feet to the point that he was unable to comfortably wear his shoes. Initially, raising his legs helped, but the swelling became more persistent. Coincidently, he began to notice increasing abdominal girth when his pants became tighter at the waist. He eventually saw his primary physician. Liver tests at this time revealed an albumin of 3.2 g/dl and mild elevations of the aminotransferases (ALT 150, AST 160). Serologic tests for viral hepatitis were reportedly negative. An abdominal ultrasound revealed an enlarged, homogeneous liver parenchyma. Diuretics (furosemide and spironolactone) were started with improvement in the patient s fluid overload state. An initial work-up for underlying cardiac disease, including an EKG, CXR, and echocardiogram, was unremarkable. PMH: Diabetes mellitus, generalized arthritis, obesity. Meds: Glyburide, Motrin PRN. SH: FH: He is married. He was born in Denmark and came to the U.S. 10 years ago. He enjoys a drink or two after work, but denies alcohol-related complications. No IVDA. A tattoo as a youth. His father passed away of alcoholic liver disease. His mother has diabetes. He has 3 healthy siblings. PE: Vital signs are normal. Moderately obese male in NAD. SKIN: Tanned-appearing. No evident vascular spiders. HEENT: No scleral icterus or oral lesions. No parotid enlargement. LUNGS: Clear bilaterally. HEART: RRR without murmur. ABD: Obese, but soft without flank or shifting dullness. An enlarged, firm liver is felt. No spleen tip. GENITALIA: Slight testicular atrophy. EXT: No clubbing or edema. Good muscle mass. Labs: - WBC 5.6, hematocrit 37%, platelets Albumin 3.2, ALT 150, AST 160, alkaline phosphatase 105, total bilirubin Prothrombin time (INR) 1.4. Ultrasound shows an enlarged, homogeneous liver. Viral hepatitis serologies were ordered and revealed: - Anti-HAV IgG positive. - HBsAg negative, HBcAb IgG negative. - Anti-HCV (ELISA) negative. What tests would you order next? What tests would you order next?

6 Serologic tests for autoimmune liver disease were ordered: - ANA negative, SMA negative. Alpha-1-antitrypsin level normal. Iron tests were ordered: - Ferritin 7,300 ng/ml, iron 220 mcg/dl, TIBC 226 mcg/dl. What do these tests suggest and what next? A serum alpha-fetoprotein was obtained and was normal. An abdominal CT scan showed no evidence of hepatic tumor. A liver biopsy was subsequently performed, and the quantitative hepatic iron was found to be 23,000 mcg/gm (dry weight). There was possible early bridging portal-toportal fibrosis, but no evidence of steatosis. What should be the management now? The patient was started on therapeutic phlebotomies with a long-term goal of maintaining the serum ferritin between ng/ml. Additionally, yearly measurement of serum alpha-fetoprotein and abdominal ultrasound was initiated for early detection of HCC or pre-cancerous dysplastic nodules. His siblings were screened for hereditary hemochromatosis. He was also advised to abstain completely from further alcohol consumption. What other interventions are necessary? Liver Tests Interpretation of Liver Tests Steven Han, M.D. Professor of Medicine & Surgery UCLA School of Medicine Liver Function Tests albumin prothrombin activity cholesterol bilirubin

7 Liver Tests AST (SGOT) ALT (SGPT) LDH Alkaline phosphatase Globulin Albumin Main export protein synthesized by the liver. Levels decreased in: Chronic liver injury Nutritional deficiency Infections Burns Renal failure Prothrombin Time Liver-synthesized coagulation factors: I, II, V, VI, IX, and X. Only substantial liver damage can prolong prothrombin time. Vitamin K deficiency may falsely prolong prothrombin time. Vitamin K deficiency Nutritional deficiency Malabsorption Antibiotics (especially cephalosporins) Bilirubin Fairly specific indicator of liver disease. In complete extrahepatic bile duct obstruction, values stabilize at mg/dl. Urine Bilirubin More sensitive for liver disease than total serum bilirubin. Presence indicates conjugated bilirubin, as unconjugated bilirubin is bound to albumin and not excreted in the urine. Aminotransferases Tests of Hepatocellular Injury AST (Aspartate aminotransferase) SGOT (serum glutamic oxaloacetic transaminase) ALT (Alanine aminotransferase) SGPT (serum glutamic pyruvic transaminase) Aminotransferases Source AST Liver Muscle (Cardiac, skeletal) Brain, kidney, pancreas, RBC s ALT More liver specific

8 Ranges of Aminotransferases FHF >10,000 Acute viral hepatitis ,000 Chronic viral hepatitis Cirrhosis Alcoholic hepatitis LDH (Lactate Dehydrogenase) Test of Hepatocellular Injury Located in liver, RBC s, muscle, kidney Isoenzyme 5 is liver LDH > ALT suggests ischemic/toxic hepatitis LDH < ALT suggests acute viral hepatitis Source Liver Bone Small bowel Placenta Alkaline phosphatase Test of Cholestasis Alkaline phosphatase Surrogate Markers Gamma glutamyl-transpeptidase Located in hepatocytes, kidneys, pancreas, heart, and brain. Levels > 3 times alkaline phosphatase suggest possible alcohol consumption. 5 nucleotidase Located primarily in hepatocytes, but also in heart and pancreas. More specific than, but equally sensitive as, alkaline phosphatase. Hepatocellular acute chronic Obstructive intrahepatic extrahepatic Infiltrative Liver Diseases Hepatocellular Disease ACUTE ALT and AST Total bilirubin Normal - Alkaline phosphatase Normal - Prothrombin Time Normal - Albumin Normal - LDH

9 Acute Hepatocellular Disease Etiologies infectious drug/toxin ischemia/shock vascular acute bile duct obstruction Wilson disease autoimmune hepatitis History Demographic characteristics Medications Concomitant medical conditions Symptoms Family history Physical Examination Usually normal Jaundice Hepatomegaly tenderness hepatic bruit Splenomegaly Mental status Acute Hepatocellular Disease Acute viral serologies Anti-HAV IgM HBsAg Anti-HBc IgM Anti-HCV HCV RNA Acute Hepatocellular Disease Other ANA Ceruloplasmin 24 hour urine for copper Hepatocellular Disease CHRONIC ALT and AST Total bilirubin Normal - Albumin Normal - Alkaline phosphatase Normal - Prothrombin activity Normal -

10 Chronic Hepatocellular Disease Viral hepatitis Alcoholic liver disease Autoimmune hepatitis Alpha 1 -antitrypsin deficiency Hemochromatosis Wilson s disease Hepatocellular Disease CHRONIC Physical findings muscle wasting vascular spiders palmar erythema signs of portal hypertension Chronic Hepatocellular Disease Viral Markers HBsAg Anti-HCV Ceruloplasmin Iron studies Anti-nuclear antibodies Alpha 1 -antitrypsin level Chronic Hepatocellular Disease Liver biopsy Imaging studies Obstructive Disease ALT and AST Normal - Total bilirubin Albumin Normal Alkaline phosphatase Prothrombin activity Normal - Obstructive Disease Intra-hepatic drugs primary biliary cirrhosis primary sclerosing cholangitis sarcoidosis lymphoma BRIC

11 Intra-hepatic Obstructive Disease Anti-mitochondrial antibodies Liver biopsy Obstructive Disease Extra-hepatic Choledocholithiasis Stricture Choledochocyst Parasite Malignancy Extra-hepatic Obstructive Disease Ultrasonography CT scan MRI/MR cholangiogram Proximal lesion percutaneous transhepatic cholangiogram Distal lesion endoscopic retrograde cholangiogram Infiltrative Disease ALT and AST Normal - Total bilirubin Normal - Albumin Normal - Alkaline phosphatase Prothrombin activity Normal Infiltrative Disease Hepatomegaly Differential Diagnosis malignancy infection amyloidosis steatosis Infiltrative Disease CT scan/ultrasound/mri Liver biopsy