Chronic Transaminitis Dr Danny Panisko UHNMSH AIMGP Seminar

Chronic Transaminitis Dr. Danny Panisko UHN/MSH AIMGP Seminar Series March 2007

Chronic Transaminitis: Objectives At the end of this seminar you will be able to: n Define chronic transaminitis n List an underlying differential diagnosis n Understand relevant features on History n Conduct a relevant Physical Exam n Describe a guideline-based Investigation approach

Chronic Transaminitis: Outline n n n n Objectives/Outline and Guidelines/References Cases Differential Diagnosis Medical History Physical Examination Initial Laboratory Evaluation Diagnostic Algorithm Revisit Objectives

Chronic Transaminitis: Guidelines n AGA Medical Position Statement: Evaluation of Liver Chemistry Tests. Gastroenterology 2002; 123: 1364 -66. Also available at www. gastro. org n AGA Technical Review on the Evaluation of Liver Chemistry Tests. Gastroenterology 2002; 123: 1367 -84. At www. gastro. org n National Academy of Clinical Biochemistry’s Laboratory Guidelines for the Screening, Diagnosis, and Monitoring of Hepatic Injury 2000; Section 4; Chronic Hepatic Injury; pp. 31 -8. At www. nacb. org

Chronic Transaminitis: Useful References n Pratt DS and Kaplan MM. Evaluation of abnormal liver-enzyme results in asymptomatic patients. N Eng J Med 2000; 342: 1266 -71 n Role of PCR and liver biopsy in the evaluation of patients with asymptomatic transaminitis: implications in diagnostic approach. J Gastroenterol Hepatol 2004; 19(11): 1291 -9 n O’Neil J and Powell L. Clinical aspects of hemochromatosis. Sem Liver Dis 2005; 25(4): 381 -91 n Giannini EG et al. Liver enzyme alteration: A guide for clinicians. CMAJ 2005; 172: 367 -79

Chronic Transaminitis: Cases n Ms. A. Viral, Miss B. Immune, and Mrs. C. Metaltoxin are three asymptomatic 35 year old women coincidently referred to your AIMGP clinic on the same day. n They were noted to have elevated transaminases (AST 100125, ALT 100 -125 [N<35]; and N ALP and Tbili) by their family MD’s on routine bloodwork 6 months ago. Repeat bloodwork, miraculously performed on the same day, revealed similar values 2 months ago and also one week ago. n The women have been well with no symptoms. They look surprisingly similar to you – maybe identical triplets lost at birth !

Chronic Transaminitis: Cases n Do these mysterious women have chronic transaminitis?

Chronic Transaminitis: Cases n Do these mysterious women have chronic transaminitis? Yes. This entity is defined as persistence of elevated ALT for more than 6 months, either after an episode of acute hepatitis or without another explanation.

Chronic Transaminitis: Cases n Why is the time frame of 6 months important ? n In general terms, what is the sensitivity this definition for chronic hepatic injury ?

Chronic Transaminitis: Cases n Why is the time frame of 6 months important ? It defines a clinical entity with a limited differential and eliminates a variety of short-lived causes of liver injury that do not have long term consequences or considerations. Work up of mild asymptomatic transaminitis that does not persist is not indicated in a patient without risk factors. Work up of chronic asymptomatic transaminitis is conducted in the hope of preventing progression to cirrhosis.

Cirrhosis:

Chronic Transaminitis: Cases n In general terms, what is the sensitivity of this definition for chronic hepatic injury ? While generally sensitive and specific, it is not perfect. For example, some patients with chronic Hepatitis C infection do not mount elevated ALT’s. Also, a patient with primary biliary cirrhosis or sclerosing cholangitis may only have an elevated ALP earlier in the course of their disease.

Chronic Transaminitis: Dxdx n In terms of broad disease categories, what is a differential diagnosis of potential etiologies of chronic transaminitis ?

Chronic Transaminitis: Dxdx n In terms of broad disease categories, what is a differential diagnosis of potential etiologies of chronic transaminitis ? Viral Immune Metal deposition / Toxic Other – including non-hepatic ! Can you provide more detail for this differential before viewing the answers on the next slide?

Chronic Transaminitis: Dxdx n Which medications, herbs, street drugs can lead to transaminitis and liver injury ? n (Note: chronic recurrent use can lead to chronic liver injury)

Chronic Transaminitis: Dxdx n Which Immune causes of liver disease can lead to chronic transaminitis ?

Chronic Transaminitis: Dxdx n Which Immune causes of liver disease can lead to chronic transaminitis ? “True” Auto-immune hepatitis Primary Biliary Cirrhosis Sclerosing Cholangitis

Chronic Transaminitis: History n Given the previously discussed differential diagnosis, what are important historical features to explore in a patient with chronic transaminitis ?

Chronic Transaminitis: History n Symptoms of liver injury: fatigue, weakness, icterus, pruritis, dark urine, possible stool colour lightening, nausea, vomiting, RUQ discomfort, intolerance to dietary protein or cigarette smoke n Symptoms of the consequences of cirrhosis: bleeding, cachexia, edema, ascites, encephalopathy, skin changes, gynecomastia etc.

Chronic Transaminitis: History n Risk factors / etiology: n n fecal/oral and blood/body fluid exchange risks for viral hepatitis drugs, medications, herbs, toxins, alcohol [CAGE], acetaminophen (primary or co-toxin) obesity, dieting, obesity surgery, bullemia, diabetes as risks for non-alcoholic steatohepatitis (NASH) Family history: for diseases with symptoms consistent for hemochromatosis, Wilson’s, alpha-1 antitrypsin, or autoimmune

Chronic Transaminitis: Physical n What physical exam features should be emphasized in a patient with chronic transaminitis ? (Can you identify the physical signs on the following slides ? )

Chronic Transaminitis: Physical Obviously trivia…. . n Dermatitis herpetiformis: chronic herpetiform lesions on extensor surfaces (in this case, elbows) in patients with Celiac Disease n Kayser-Fleischer Rings, best appreciated with a slit lamp, as brown pigmentary deposits on the periphery of the cornea, in patients with Wilson’s disease n Tendon xanthomata, on the Achilles, in patients with hyperlipidemia due to cholestasis in liver disease that also can have chronic transaminitis such as primary biliary cirrhosis

Chronic Transaminitis: Physical n n n Findings of liver injury and structural change: hepatomegaly, RUQ tenderness Findings of liver dysfunction: icterus/jaundice, edema, bleeding, bruising, edema, encephalopathy, asterixis, fetor hepaticus Findings of portal hypertension: splenomegaly, caput medusa, hemorrhoids, ascites Stigmata of chronic liver disease Findings of Etiologic disease processes: bronze diabetes, mental status changes/psychoses, malnutrition/malabsorption, vasculitic purpura (what are the connections with these signs ? )

Chronic Transaminitis: Case History and Physical n No additional history or physical exam data was contributory for none of the suspiciously similar Ms. A. Viral, Miss B. Immune, nor Mrs. C. Metaltoxin…. except that Ms. A. Viral received a transfusion of 2 units of p. RBC’s after a car accident in 1986, and Mrs. C. Metaltoxin underwent a total hysterectomy because of fibroids at age 30

Chronic Transaminitis: Initial Labs n What are considered relevant initial laboratory investigations by several expert consensus guidelines ?

Chronic Transaminitis: Initial Labs n What are considered relevant initial laboratory investigations for chronic transaminitis by several expert consensus guidelines ? Liver enzymes, INR, Albumin, CBC with platelets, Hepatitis B S Ag, Hepatitis B S Ab, Hepatitis C Ig. G, % Iron Saturation and/or Ferritin

Chronic Transaminitis: Initial Labs n Ms. A. Viral was found to have Hepatitis C Ig. G positive. Therefore, a diagnosis of Chronic Hepatitis C was made. She was referred to a hepatologist for consideration of antiviral therapy. n Mrs. C. Metaltoxin was found to have an iron saturation of 58% (n<45%) and a ferritin of 850 mcg/l (n = 22 -322) … n n n What is her diagnosis ? Does she need further diagnostic testing ? What are the broad principles in her management ?

Chronic Transaminitis: Mrs. C. Metaltoxin n She likely has hereditary hemochromatosis, was not on iron supplements, & did not take alcohol to excess (why is this relevant ? ) n Some physicians like to confirm the degree of iron overload definitively with liver biopsy n She and her first degree relatives should receive genetic screening, with HFE mutation analysis, to facilitate decision making for treatment of family members and genetic counseling n Treat with phlebotomy get Fe saturation below 50%, & assess for cirrhosis and other systemic involvement of Fe overload

Chronic Transaminitis: Diagnostic Algorithm n Miss B. Immune had (N) initial investigations apart from a repeat of the transaminases which were minimally elevated as before… n What should be done now ?

Chronic Transaminitis: Diagnostic Algorithm n The AGA algorithm suggests abdominal ultrasound, ANA, Ceruloplasmin, anti-smooth muscle antibody, anti-gliadin antibody, anti-endomysial antibodies and alpha-1 antitrypsin level. (What entities do these investigations test for ? … see answer on next slide) n The algorithm also suggests further confirmatory liver biopsy if any of these results are abnormal. Many hepatologists would also do a liver biopsy at this point if there was still no diagnosis. (See algorithm on 2 nd slide following)

Chronic Transaminitis: Miss B. Immune n Miss B. Immune had a positive ANA at a titre of 1: 640. n A liver biopsy confirmed autoimmune hepatitis with no evidence of cirrhosis. n She was referred to a hepatologist and started on Prednisone therapy.

Chronic Transaminitis: Objectives Hopefully, you are now able to: n Define chronic transaminitis n List an underlying differential diagnosis n Understand relevant features on History n Conduct a relevant Physical Exam n Describe a guideline-based Investigation approach