Harvard Medical School

Transcription

1 Harvard Medical School

2 Evaluation of Abnormal Liver Tests in the Primary Care Setting C. Christopher Smith, MD, FACP Associate Professor of Medicine, Harvard Medical School Beth Israel Deaconess Medical Center

3 Disclosure of Financial Relationships C. Christopher Smith, M.D. Has no relationship with any entity producing, marketing, reselling or distributing health care goods or services consumed by, or used on patients.

4 Case A 56-year-old woman with a history of hypothyroidism and hypertension presents with acute onset of mid-back pain; it began three days ago when she attempted to open a window that was stuck closed. The pain has not been fully relieved with NSAIDs. Other than a pruritic rash on her extensor surface of her right elbow, and occasional diarrhea due to her lactose intolerance, she has no complaints. Examination is remarkable for mid spine tenderness to percussion and the rash on her elbow and back (next slide). BMI is 22.

5 An example of her rash Courtesy Dr. Ciaran Kelly

6 An example of her spinal imaging

7 Case continued Laboratory studies: Hematocrit : 31% Hemoglobin: 10.1 g/dl Platelet count: 260,000 MCV: 78 fl Ferritin: 10 ng/ml ALT: 62 U/L AST: 51 U/L Alkaline phosphatase: 110 U/L TSH, serum calcium, albumin, PT: normal

8 Case Continued Patient is post-menopausal and has no abnormal vaginal bleeding; she denies melena or BRBPR. She undergoes a colonoscopy. The colonoscopy is normal and random biopsies are without abnormalities.

9 Case What diagnosis will most likely account for her symptoms and findings? a. Myelodysplastic syndrome b. Cirrhosis c. Celiac disease d. Lymphoma

10 Case What diagnosis will most likely account for her symptoms and findings? a. Myelodysplastic syndrome b. Cirrhosis c. Celiac disease d. Lymphoma

11 Case Summary: 52-year-old female with new compression fracture, anemia, elevated liver enzymes, and rash on extensor surfaces and on back What is the most likely diagnosis that will tie together all of these findings? What is the best way to confirm this diagnosis?

12 Celiac Disease Autoimmune disorder Tissue transglutaminase (ttg) is the auto-antigen Cross links collagen Antibodies react to ttg inducing a change in charge and structure of gluten Allowing gluten to bind to HLA DQ2 and DQ8 receptors Triggering immune response with cytokine release and lymphocyte infiltration enteropathy Intolerance to gluten: wheat, rye and barley

13 Celiac Disease Classic Symptoms Diarrhea/Malabsorption Iron deficiency anemia Abdominal Pain Weight Loss Fatigue/lethargy Bloating/Gas Dermatitis Herpetiformis Non-Classic Symptoms Aysmptomatic LFT elevations Aphthous ulcers Alopecia Osteopenia/osteoporosis Infertility Dental defects Neuropathy

14 Dermatitis Herpetiformis ttg found in many organs, including skin Antibodies to intestinal ttg can cross-react to skin ttg causing inflammation Pruritic papules, vesicles and macules on extensor surfaces

15 Dermatitis Herpetiformis Courtesy Dr. Ciaran Kelly

16 Audience Question Which region has the lowest prevalence of celiac disease? a. North America b. Europe c. Northern India d. South East Asia e. North Africa

17 Audience Question Which region has the lowest prevalence of celiac disease? a. North America b. Europe c. Northern India d. South East Asia e. North Africa

18 Celiac Disease: Epidemiolgy 1% of the general population (1:100) 10% if first degree relative affected Risk of celiac disease in the following conditions: Chronic diarrhea: 25% Iron deficiency anemia: 10% Any autoimmune disorder: 5% Type I diabetes mellitus: 5% Osteoporosis: 3% More prevalent than Crohn s disease, ulcerative colitis and type 1 diabetes mellitus combined Fasano, Arch Intern Med 2003

19 Recent increase in celiac disease diagnosis (BIDMC, Boston) Courtesy Dr. Ciaran Kelly

20 When to test for Celiac Disease Diarrhea +/- malabsorption IBS like (e.g., mild diarrhea and bloating) Lactose intolerance like but not responding to lactose free diet Nutritional deficiencies Iron deficiency anemia (most common), B12, folate Vitamin D with osteopenia/osteoporosis Other Dermatitis herpetiformis Impaired fertility Ataxia, peripheral neuropathy Severe aphthous stomatitis Abnormal LFTs

21 Audience Question Our patient s anti-ttg returns negative. What is the next step that should be performed? a. Immediately initiate a gluten free diet anyway b. Perform an upper endoscopy with small bowel biopsies c. Perform IgA d. B and C

22 Audience Question Our patient s anti-ttg returns negative. What is the next step that should be performed? a. Immediately initiate a gluten free diet anyway b. Perform an upper endoscopy with small bowel biopsies c. Perform IgA d. B and C

23 Celiac Disease: Diagnosis IgA-tTG is the test of choice Sensitivity/specificity 95% 5-10% of patients with celiac sprue are IgA deficient Patient should not be on gluten diet Must confirm with small bowel biopsy

24 Normal Small Intestine Courtesy of Dr. Ciaran Kelly

25 Subtotal Villous Atrophy in Celiac Sprue Courtesy of Dr. Ciaran Kelly

26 Small intestinal biopsy histology: the diagnostic gold standard Healthy Villi Celiac Disease

27 Diagnosing Celiac Disease CD present CD absent Positive ttg Negative ttg Assume high risk population with 10% risk and a ttg sensitivity and specificity of 95% NPV: TN/FN+TN: 855/860:99%; PPV: TP/FP+TP: 95/140:68%

28 Diagnosis of Celiac Disease Consider a diagnosis of celiac disease <10% Determine pretest probability >10% Serum IgA TTG Negative Diagnosis adequately excluded Positive SI biopsy histology Negative Diagnose Celiac disease Serum IgA TTG & SI biopsy histology Positive Adapted from: Kelly et al; Up-to-date 1998, Am J GE 2001, NEJM 2002

29 Case Summary 56 year old female with prior elevations of ALT/AST thought to be due to celiac disease. Liver studies completely normalized after treatment for celiac disease. Now on strict gluten free diet and normalized TTG After many months on a gluten free diet, the patient is gaining weight. To combat this she has begun an aggressive exercise regimen. She is now found to again have elevation of LFTs (ALT 47; AST 42). Alkaline phosphatase and bilirubin are normal.

30 Audience Question What is the most likely underlying diagnosis and how will you confirm? a. Plan for cholangiogram for primary sclerosing cholangitis b. Check ceruloplasmin for Wilson s disease c. Check AMA for Primary Biliary Cirrhosis d. Check CPK for muscle injury e. Counsel patient on alcohol use

31 Audience Question What is the most likely underlying diagnosis and how will you confirm? a. Plan for cholangiogram for primary sclerosing cholangitis b. Check ceruloplasmin for Wilson s disease c. Check AMA for Primary Biliary Cirrhosis d. Check CPK for muscle injury e. Counsel patient on alcohol use

32 Causes of abnormal ALT/AST with normal liver biopsy Muscle Exercise induced or Metabolic Disorder Both ALT and AST can be elevated Check CPK Celiac Addison s Disease Thyroid Bardella, Hepatology 1999

33 Wilson s Disease Rare genetic disorder of reduced biliary copper excretion and increased deposition Cognitive changes; hemolytic anemia, cardiomyopathy Rare in patients over the age 40 Decreased ceruloplasmin levels (screening test) Reduced in 85% of affected patients Ophthalmologic examination for Kayser-Fleischer rings AST/ALT: mild elevation to fulminant hepatic failures 24 urine for quantitative copper excretion Frequently have low alkaline phosphate Low serum uric acid

34 Primary Biliary Cirrhosis Autoimmune condition leading to progressive destruction of bile ducts Resulting in chronic cholestatic liver disease 90% women between years of age Presenting symptoms: pruritis, fatigue, fat malabsorption, hypercholesterolemia Asymptomatic elevation in serum alkaline phosphatase (often 10x normal) Elevated IgM Anti-mitochondrial antibodies (AMA) Titers > 1:40 in greater than 90% of patients with PBC

35 Primary Sclerosing Cholangitis Almost exclusively in patients with IBD, especially men with ulcerative colitis Present with isolated alkaline phosphatase Pruritis Steatorrhea Vitamin deficiency Diagnosis through cholangiography No confirmatory serologic test No effective treatment

36 PSC and PBC PBC PSC Demographic Asymptomatic women IBD esp. UC/men Laboratory findings alk phos/igm alk phos Serologic Studies AMA none Diagnosis Liver Biopsy Cholangiography Treatment Ursodeoxycholic Acid None

37 Alcohol Abuse AST:ALT greater than 2 > 90% of patients with this ratio have alcoholic liver disease > 96% when ratio > 3:1 Both less than 300 IU/L Ɣ-glutamyltransferase Twice the ULN strongly support the diagnosis Poorly specific so should not be used as a single test Cohen, Dig Dis Sci 1979

38 Hemochromatosis Common genetic disorder characterized by increased intestinal absorption of iron 10% Caucasians heterozygous 0.5% homozygous Excess iron deposition in liver, heart, pancreas and pituitary Cirrhosis, heart disease, arthropathy, hypogonadism, thyroid dysfunction, skin pigmentation & type 1 diabetes mellitus Cost-effective screening starts with serum iron and TIBC Iron saturation > 45% is suggestive of hemochromatosis Ferritin is less specific as it is an acute phase reactant If iron saturation elevated, test for mutations of HFE gene C282Y homozygrous or compound heterozygote C282Y/H63D

39 Case A 67-year-old man just moved to your city and presents as a new patient. He has no complaints. His history is significant for type II diabetes (controlled with diet; last HgbA1c 6.9%). He has never had more than one beer a day. Examination is remarkable for a BMI of 33. Laboratory studies of note include platelet count: 89,000; ALT: 125; AST: 132 Alk phos, bilirubin, viral serologies, iron saturation: normal Albumin 3.1 Liver ultrasound shows diffuse fatty infiltration of the liver

40 Audience Question In addition to weight loss, which of the following is the most appropriate next step in managing this patient s abnormal liver studies? a. Initiate insulin sensitizing medication (e.g., metoformin or pioglitazone) and repeat liver studies in six months b. Refer for a liver biopsy c. Counsel patient on his alcohol consumption d. Send serum ceruloplasmin levels

41 Audience Question In addition to weight loss, which of the following is the most appropriate next step in managing this patient s abnormal liver studies? a. Initiate insulin sensitizing medication (e.g., metoformin or pioglitazone) and repeat liver studies in six months b. Refer for a liver biopsy c. Counsel patient on his alcohol consumption d. Send serum ceruloplasmin levels

42 Case Highlights 67-year-old obese patient with type II diabetes AST:ALT ratio > 1 Limited alcohol intake Ultrasound with steatosis Reasonable evaluation of common causes of liver abnormalities is unrevealing What is the best next step in management?

43 Nonalcoholic Steatohepatitis (NASH) Most common cause of abnormal transaminase levels 30% of Americans have non-alcoholic fatty liver 5% will develop nonalcoholic steatohepatitis 8-26% of pts with NASH will develop cirrhosis Leading cause of cryptogenic cirrhosis No clinical or laboratory feature can predict progression Associated conditions: Obesity (69-100%) Type 2 diabetes (34-75%) Hyperlipidemia (20-80%) Angulo, NEJM 2002

44 Nonalcoholic Steatohepatitis (NASH) Diagnosis of NASH is one of exclusion Most patients are asymptomatic AST/ALT ratio less than 1 If ratio reverses, worrisome for development of cirrhosis Normal serum aminotransferases do not exclude presence of advanced liver disease Liver ultrasound is highly sensitive for steatosis but not specific for cause of steatosis or presence fibrosis or more advanced liver disease No distinguishing historical or laboratory features to differentiate from other causes of chronic liver disease

45 Nonalcoholic Steatohepatitis (NASH) Differential Diagnosis Alcohol and drug related liver disease: careful history Hepatitis B and C (HBV surface ag and HCV ab) Hereditary hemochromatosis (Fe:TIBC) In right clinical setting consider other causes Liver biopsy is only way to confirm diagnosis of NASH However, high risk to benefit ratio for biopsy as most patients do not progress and frequently does not change management Consider biopsy if suspect NASH and one of the following: Laboratory or PE findings of chronic liver disease Unexplained findings (i.e., elevation of ANA or iron studies) Other RF: Age > 45, Obesity, AST: ALT > 1, Type II DM

46 Nonalcoholic Steatohepatitis (NASH) Treatment is directed at risk factor modification Weight loss, lipid control, diabetes control Insulin sensitizing drugs: pioglitazone or metformin Limited data Belfort, NEJM 2006

47 Case A 34-year-old woman with a history of hypothyroidism and hemolytic anemia presents with several months of fatigue. Four months ago she had a serum alanine aminotransferase (ALT) of 425 U/L, with normal TSH, bilirubin, and alkaline phosphatase. Examination is remarkable for the liver edge three cm below the costal margin. Laboratory studies: ALT: 923 AST: 801 Total Bilirubin: 2.2 Alkaline Phosphatase: 98 PT and albumin: normal

48 Case continued Labs continued: Ferritin: 310 ng/ml (normal < 300) Plasma ceruloplasmin: 32 mg/dl Antimitochondrial ab: negative Anti-smooth muscle ab: 1:1280 Hepatitis A, B, C: negative Liver Biopsy: periportal and bridging necrosis

49 Case Which is the most appropriate treatment for this patient? a. Bile salts b. Phlebotomy to reduce iron levels c. Interferon alfa d. Prednisone e. Penicillamine

50 Case Which is the most appropriate treatment for this patient? a. Bile salts b. Phlebotomy to reduce iron levels c. Interferon alfa d. Prednisone e. Penicillamine

51 Case Highlights 34 year old women with history of hypothyroidism with 4+ month history of hepatitis Now with normal AMA, ceruloplasmin Ferritin mildly elevated Negative viral serologies ALT now Anti-smooth muscle (ASMA): 1:1280 Biopsy shows periportal and bridging necrosis What treatment?

52 Liver Transaminase Levels > 500 Common Acute Viral Hepatitis Drug/toxin induced liver injury Especially acetaminophen Amanita phalloides Ischemic hepatitis Severe auto-immune hepatitis Less Common Common Bile Duct Stone Budd-Chiari or Veno-occlusive disease Acute Fatty Liver of Pregnancy or HELLP Wilson s disease

53 Causes of Fulminant Liver Failure A B C D E F G H Acetaminophen, Hep A, Autoimmune Hep B Hep C Hep D, Drugs Hep E, Esoteric causes (Wilson s, Budd-Chiari) Fatty infiltration (acute fatty liver of pregnancy) (only knows) Herpes simplex virus Dr. Sanjiv Chopra's Liver Book: A Comprehensive Guide to Diagnosis, Treatment, and Recovery

54 First, make the diagnosis Differential Diagnosis includes: Primary biliary cirrhosis AMA was negative Primary sclerosing cholangitis No history of IBD Viral hepatitis Serologies negative Wilson s disease Ceruloplasmin normal

55 First, make the diagnosis Nearly 10% of chronic hepatitis is caused by autoimmune hepatitis Type I: classic form, accounts for most in US Female predominance Extrahepatic autoimmune manifestations Tests: + ANA > 1:160 or ASMA > 1:40 and hypergammaglobulinemia (associated with auto-antibodies) Type II: less common Presents earlier and progresses more rapidly ANA, ASMA negative but + anti-lkm > 1:20 Heterogeneous and fluctuating nature Often other autoimmune features in over a third

56 Next, assess severity of disease She has very high ALT 10-20X normal, increasing Characteristically transaminase levels are out of proportion to bili or alk phos She has systemic symptoms She has fatigue; can also see anorexia, arthralgia, myalgia, fever, jaundice Biopsy shows an aggressive case in which inflammatory reaction bridges portal tracts (= bridging necrosis) Treat!

57 Treatment of Autoimmune Hepatitis Type I is very responsive to glucocorticoid therapy Long-term remission is seen on low-dose prednisone Start at mg/d and taper Maintain on 5 mg/d 20 mg/d until in remission 6-24 months, then taper Restart if recurs Can use steroid sparing agents (azathioprine, etc) in select patients

58 Audience Question In a patient with asymptomatic elevation in ALT/AST, and auto-immune hepatitis is suspected, which is the best screening test? a. Hypergammaglobulin (> 1.5 x the ULN) b. Antinuclear antibody (ANA) titers c. Anti-smooth muscle antibody titers (ASMA) d. Ferritin level e. ESR

59 Audience Question In a patient with asymptomatic elevation in ALT/AST, and auto-immune hepatitis is suspected, which is the best screening test? a. Hypergammaglobulin (> 1.5 x the ULN) b. Antinuclear antibody (ANA) titers c. Anti-smooth muscle antibody titers (ASMA) d. Ferritin level e. ESR

60 Diagnosing Auto-immune Hepatitis Serum protein electrophoresis is a useful screening test > 80% of patients with autoimmune hepatitis have hypergammaglobulinemia Polyclonal immunoglobulins > 2 x ULN is most suggestive ANA: 28% sensitive ASMA: 40% sensitive Czaja, Semin Liver Dis, 1984

61 A patient presents to your clinic A 34 year old female presents to your clinic to establish care with her new PCP. She has no complaints or significant past medical history, but is seeking prenatal counseling. She was born and raised in China, but has been in the United States for the last 10 years and works in the healthcare industry. You check a hepatitis B panel with the following results: HBsAg: positive HBcAb: positive HBsAb: negative

62 Questions How did she acquire HBV? Is she at risk for transmission to others? Does how and when she acquired HBV alter outcomes? How does HBV compare and contrast to HCV? What is the difference between HBV carrier and HBV (chronic) infection and why does it matter? What other studies should be performed?

63 Hepatitis B Worldwide HBV accounts for over a million deaths annually 2 billion with past/present infection 350 million actively infected worldwide (5% of world population) Leading cause of chronic hepatitis, cirrhosis and hepatocellular carcinoma (15-40%) Hepatocellular carcinoma has increased worldwide, killing 300,000 to 500,000 each year Prevalence varies by region Greatest in Southeast Asia, China, Africa and Alaska More than half the population infected at some point 8% chronic carriers Maynard, Vaccine,

64 Prevalence of Chronic Hepatitis B CDC Travelers Health: Yellow Book, 2008

65 High Risk Groups for HBV Injection drug use Healthcare and public safety workers Hemodialysis patients History of STD Men who have sex with men Sex contacts of infected persons or multiple sex partners Infants born to infected mothers Children of immigrants from endemic country Household contact of chronically infected persons CDC. Hepatitis B Fact Sheet, 2004

66 2002 Transmission Factors of HBV in U.S. CDC Hepatitis Surveillance Report, 2004

67 HBV vs. HCV Much more contagious and easily spread than HCV 1,000,000 HBV virons for every HCV viron Present in all bodily secretions except for feces HBV is very hardy Higher prevalence of HCV in U.S. - 2% vs. 0.5% Higher prevalence reflects natural history of disease

68 HCV Course Rarely fulminant and fatal Acute infection causes symptoms in <20% After acute infection, 20% clear virus from blood and have full recovery Remaining 80% have viremia that persists for life Seroconversion (positive antibody test) may take 3 months

69 Natural History of Hepatitis C Exposure HCV Annual rate 80% Chronic HCV Infection 20 years Cirrhosis 20% Decompensation 6% HCC 4% Death 4%

70 % Developing Chronic Infection Age and Mode of Acquisition of HBV Development of chronic infection varies by mode and age of transmission Perinatal infection (most common mode of transmission worldwide) 90% develop chronic infection Acquired between ages 1 and 5 years % risk Adult acquisition: <5% risk of chronic infection Neonate Infant Adult Stevens, NEJM, 1975 Beasley, J Infect Dis 1983

71 Outcomes of Acute Hepatitis B Recovery Subclinical Acute Hepatitis Fulminant Hepatitis Chronic Infection Ostapowicz, Ann Intern Med, 2002

72 Outcomes of Chronic Hepatitis B Chronic HBV Inactive Carrier (nonreplicative) Chronic Hepatitis (replicative) Cirrhosis Hepatocellular Carcinoma

73 Diagnosis of Hepatitis B Serologic Marker HBsAg anti-hbs HBeAg anti-hbe anti-hbc IgM anti-hbc IgG & HBsAg anti-hbc IgG & anti-hbs HBV-DNA Clinical Significance Acute/Chronic Infection Immunity High infectivity Low infectivity Acute Infection Chronic Infection Resolved Infection Viral replication/correlates with infectivity

74 Serology Cases HBsAg Anti-HBs Anti-HBc + - IgM a. Acute HBV Infection b. Exacerbation of Chronic Hepatitis B c. Remote Past Infection d. A or B

75 Serology Cases HBsAg Anti-HBs Anti-HBc + - IgM a. Acute HBV Infection b. Exacerbation of Chronic Hepatitis B c. Remote Past Infection d. A or B

76 Causes of Acute Hepatitis in HBsAg positive Patients Acute HBV infection anti-hbc IgM Seroconversion HBeAg anti-hbe HBV reactivation Superinfection HAV HDV HCV Non-viral liver injury Drugs Toxins

77 Serology Cases HBsAg Anti-HBs Anti-HBc - + IgG a. Active infection b. Remote past infection c. Window period following acute infection d. Patient immune due to vaccination

78 Serology Cases HBsAg Anti-HBs Anti-HBc - + IgG a. Active infection b. Remote past infection c. Window period following acute infection d. Patient immune due to vaccination

79 Serology Cases HBsAg Anti-HBs Anti-HBc Vaccination with no prior exposure to HBV

80 Serology Cases HBsAg Anti-HBs + + a. Recovery phase of acute infection b. Remote infection that has cleared c. Chronic HBV infection with HBsAb directed against different subtypes d. A or C

81 Serology Cases HBsAg Anti-HBs + + a. Recovery phase of acute infection b. Remote infection that has cleared c. Chronic HBV infection with HBsAb directed against different subtypes d. A or C

82 Serology Cases HBsAg Anti-HBs Anti-HBc Which of the following would explain the above scenario? A. Low level HBV carrier B. Remote past infection (recovered HBV) C. False positive test result D. Window phase of acute hepatitis B E. Any of the above

83 Serology Cases HBsAg Anti-HBs Anti-HBc Which of the following would explain the above scenario? A. Low level HBV carrier B. Remote past infection (recovered HBV) C. False positive test result D. Window phase of acute hepatitis B E. Any of the above

84 A 46-year-old woman with a 4-year history of chronic HBV and substance abuse is admitted with 3 days of jaundice, fatigue, and nonbloody vomiting. She does not take medications (including no acetaminophen). She reports drinking four shots of whiskey a day, with ongoing intravenous use of heroin. Her vital signs are stable. She is icteric. Abdominal examination reveals a smooth liver edge one cm below the costal margin but no splenomegaly or ascites. No manifestations of cirrhosis.

85 Patient value Reference ALT AST Alk phos Total bili Albumin INR 1.3 Hep A IgM: Neg; IgG: Pos HBV: sag: Pos; core IgG Ab: Pos; core IgM Ab: Neg; e Ag: Neg HBV DNA Viral Load: 1200 HCV: Ab: Neg; RNA: Neg

86 Which one of the following diagnoses is most likely? a) Alcoholic hepatitis b) Hepatitis E virus infection c) Hepatitis B virus reactivation d) Hepatitis D virus infection e) Ischemic hepatitis

87 Which one of the following diagnoses is most likely? a) Alcoholic hepatitis b) Hepatitis E virus infection c) Hepatitis B virus reactivation d) Hepatitis D virus infection e) Ischemic hepatitis

88 Causes of Acute Hepatitis in HBsAg positive Patients Acute HBV infection anti-hbc IgM Seroconversion HBeAg anti-hbe HBV reactivation Superinfection HAV HDV HCV Non-viral liver injury Drugs Toxins

89 Hepatitis A Spread via fecal-oral route Person to person Homosexual contact Institutional transmission Daycare centers Contaminated food or water (inadequate sanitation, undercooked shellfish or infected food handlers)

90 Hepatitis A Usually acute, self-limited illness More symptomatic in adults Marked elevation aminotransferases and bilirubin <1% fulminant hepatic failure More common in patients with underlying liver disease Serum IgM anti-hav in acute setting

91 Hepatitis D Parenteral transmission Anti-HDV may appear late Especially true in immunodeficient patients Defective virus Requires HBV to complete virion assembly and secretion Therefore, HBV must be present Progresses to chronic HDV infection Suppression of HBV replication Accelerated course to cirrhosis

92 Hepatitis E Spread by fecal-oral route Most common by fecally contaminated water Self-limited illness More severe course than HAV Fulminant hepatitis 0.5-3% 15-25% mortality in pregnancy

93 Laboratory Tests to Assess Asymptomatic Patient with Elevated Aminotransferase Levels Initial Tests HCV ab HBV sag, sab coreab Iron and TIBC Serum ceruloplasmin Serum protein electrophoresis Additional Tests TTG CPK TSH Alpha1-antitrypsin phenotyping

94 Questions from the Audience?

95