Chronic Transaminitis

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Chronic Transaminitis: Objectives. At the end of this seminar you will be able to:Define chronic transaminitisList an underlying differential diagnosisUnderstand relevant features on HistoryConduct a relevant Physical ExamDescribe a guideline-based Investigation approach. Chronic Transaminitis
Chronic Transaminitis

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

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

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

4. Chronic Transaminitis: Guidelines AGA Medical Position Statement: Evaluation of Liver Chemistry Tests. Gastroenterology 2002; 123: 1364-66. Also available at www.gastro.org AGA Technical Review on the Evaluation of Liver Chemistry Tests. Gastroenterology 2002; 123: 1367-84. At www.gastro.org 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

5. Chronic Transaminitis: Useful References Pratt DS and Kaplan MM. Evaluation of abnormal liver-enzyme results in asymptomatic patients. N Eng J Med 2000; 342: 1266-71 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 O?Neil J and Powell L. Clinical aspects of hemochromatosis. Sem Liver Dis 2005; 25(4): 381-91 Giannini EG et al. Liver enzyme alteration: A guide for clinicians. CMAJ 2005; 172: 367-79

6. Chronic Transaminitis: Cases 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. They were noted to have elevated transaminases (AST 100-125, 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. The women have been well with no symptoms. They look surprisingly similar to you ? maybe identical triplets lost at birth !

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

8. Chronic Transaminitis: Cases 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.

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

10. Chronic Transaminitis: Cases 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.

11. Cirrhosis:

12. Chronic Transaminitis: Cases 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.

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

14. Chronic Transaminitis: Dxdx 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?

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

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

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

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

21. Chronic Transaminitis: History 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 Symptoms of the consequences of cirrhosis: bleeding, cachexia, edema, ascites, encephalopathy, skin changes, gynecomastia etc.

22. Chronic Transaminitis: History Risk factors / etiology: 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

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

27. Chronic Transaminitis: Physical Obviously trivia?.. Dermatitis herpetiformis: chronic herpetiform lesions on extensor surfaces (in this case, elbows) in patients with Celiac Disease 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 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

28. Chronic Transaminitis: Physical 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 ?)

29. Chronic Transaminitis: Case History and Physical 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 pRBC?s after a car accident in 1986, and Mrs. C. Metaltoxin underwent a total hysterectomy because of fibroids at age 30

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

31. Chronic Transaminitis: Initial Labs 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 IgG, % Iron Saturation and/or Ferritin

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

33. Chronic Transaminitis: Mrs. C. Metaltoxin She likely has hereditary hemochromatosis, was not on iron supplements, & did not take alcohol to excess (why is this relevant ?) Some physicians like to confirm the degree of iron overload definitively with liver biopsy 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 Treat with phlebotomy get Fe saturation below 50%, & assess for cirrhosis and other systemic involvement of Fe overload

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

35. Chronic Transaminitis: Diagnostic Algorithm 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) 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 2nd slide following)

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

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


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