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CPC as Cinema

CPC as Cinema. “The Producers”, starring Drs. Troy Wadsworth and Nilam Soni “Clueless”, starring Mark Feldman “The Sting”, starring Dr. Dale Odell. 45 year old divorcee with acute delirium associated with hepatic disease (jaundice, abnormal liver chemistries and asterixis).

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CPC as Cinema

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  1. CPC as Cinema • “The Producers”, starring Drs. Troy Wadsworth and Nilam Soni • “Clueless”, starring Mark Feldman • “The Sting”, starring Dr. Dale Odell

  2. 45 year old divorcee with acute delirium associated with hepatic disease (jaundice, abnormal liver chemistries and asterixis). Asterixis (liver flap) Hepatic failure Respiratory acidosis Uremia Cerebrovascular disease The Plot:

  3. The Setting • Polysubstance abuse [nicotine, alcohol, iv cocaine, pot] • Bipolar disorder • Taking at least 6 other drugs: • hydrocodone and acetaminophen for back pain • risperidone, citalopram, carbamazepine, nefazodone •  she is prone to drug OD if depressed • Grave’s disease treated with RAI twice- currently on T4

  4. GENERAL: icteric, overweight VITALS: afebrile; + tilt HEENT: dry mucosae; blood in mouth and on chin; poor dentition CHEST: normal ABDOMEN: mild RUQ tenderness; 8 cm liver; no ascites/splenomegaly EXTREMITIES: no edema NEURO: alert but agitated and disoriented; asterixis Her exam findings

  5. Laboratory test abnormalities • Liver: bili 5.5, ALT 3,539, AST 2,233, AP 253, NH3 59, PT/INR 26.3/2.1, Alb 3.0, TP 6.2, Glob 3.2, platelets 274K, Hgb 12.3 • Other: Anion gap 14; K 3.2, P 2.3, TSH 0.06 uIU/mL (all low). • Renal/urine: BUN 49, Creatinine 3.3, ratio 15:1, small bilirubin, SG 1.023, 17 WBC, 8 RBC, mod bacteria, + nitrite, urobilinogen > 8 mg/dL (normal, 0.1-1.0 mg/dL)

  6. High Urine Urobilinogen  our patient has liver disease, hemolysis, or both

  7. Toxicology studies • Opiates (expected, hydrocodone) • APAP - [  not cause of her liver disease] • Aspirin - [ not cause of her gap acidosis] • Carbamazepine- slightly toxic range signs of toxicity: clumsy, unsteady,confused,dizzy,drowsy • ? due to OD, liver failure with  metabolism, or drug-drug interaction with nefazodone • Nefazodone-induced carbamazepine toxicity. Am J Psychiatry 153: 733, 1996 • Cabamazepine-nefazodone interaction in healthy subjects. J Clin Psychopharmacol 20: 46-53, 2000 • ? role of carbamazepine in causing liver failure

  8. Why this looks like acute liver failure • Short history of encephalopathy • No ascites, splenomegaly, spider angiomas, or laboratory signs of chronic liver disease (e.g., thrombocytopenia, anemia) • Slightly low albumin, markedly depleted hepatic-derived clotting factors

  9. Half lives of certain proteins synthesized in the liver • Albumin: 18 days • Fibrinogen (factor I): 3-5 days • Prothrombin (factor II): 2-5 days • Factor X: 1-2 days • Factor IX: 18-24 hours • Factor VII: 8-12 hours

  10. Systems involved (when consid-ering her differential diagnosis) • Liver, acute fulminant process • Brain (hepatic encephalopathy vs other) • Neurologic: falls, dysarthria • Psychiatric: bipolar disorder • Kidneys • acute renal failure. presumably • abnormal urinary sediment

  11. Causes of acute liver failure in US and other Western nations • Acetaminophen hepatotoxicity 34% • Acute viral hepatitis (B > A>> others) 25% • Unknown causes (cryptogenic) 19% • Other, known causes 12% • AIH, Wilson disease • Budd-Chiari, AFLP, liver cancer, liver ischemia, Reye’s • Other drugs (non-APAP) or toxins 10% • Drugs • Toxins: mushrooms, CCl4, sea anemone sting

  12. Five factors predicting high mortality in patients with fulminant hepatic failure (non-acetaminophen) • Negative serologic tests for HAV and HBV  • Age < 10 or > 40 * • Jaundiced > 7 days before encephalopathy • Prothrombin time (PT) > 50 seconds • Total serum bilirubin > 17.6 mg/dL 1 factor  80% mortality without OLT 3 factors, or PT > 100 seconds  >95% mortality [O’Grady et al. King’s College (London) data base of 588 patients with fulminant hepatic failure. Gastroenterology 97: 439, 1989]

  13. PROS: most common cause of icteric illness with high transaminases history of IVDU and tattoos anti-HCV is not highly sensitive for acute C CONS: all tests for A-E viruses were negative HCV RNA not given; however, severity of liver disease with encephalopathy is un-common with acute C Acute viral hepatitis A-E

  14. PROS: demographics history of Grave’s very high AST/ALT presentation with liver failure is possible in AIH CONS: no ANA, ASMA mentioned normal serum globulins other organ systems involved Autoimmune hepatitis (AIH)

  15. Wilson disease • Autosomal recessive; 1/30,000 in all ethnic groups; 1 in 90 carry a mutated Wilson disease gene (ATP7b) • ATP7b (13q14) codes for a trans-Golgi P-type ATPase, with 6 copper binding sites • Gene is expressed in liver, kidney, and placenta • Mutations in ATP7b lead to copper accumulation in liver, kidney, brain, and cornea • > 200 mutations have been reported, most in single families, but certain mutations have been reported in many families, such as H1069Q, found in 40% of Caucasians • Hepatic expression of ATP7b facilitates copper excretion into bile and copper attachment to apoceruloplasmin and genesis of ceruloplasmin for transport to tissues

  16. COPPER (unabsorbable) apical bile ? blood ceruloplasmin vesicles murr 1 apoceruloplasmin Liver Cell ATP7b WILSON Golgi network atox 1 chaperone COPPER Ctr 1 sinusoidal Diet  Upper GI absorption  portal vein periphery (His-Cu) (Alb-Cu,His-Cu)

  17. Wilson disease: presentations • Progressive neurological disorder, without clinically prominent liver disease • as described by Wilson (1912), an American-born neurologist practicing in Britain who called the disease progressive lenticular degeneration • Liver disease only, fulminant ( F > M ) or chronic • Psychiatric illness • Isolated acute hemolysis • Combinations of the above

  18. Proposed Classification(Ferenci et al. Liver Int’l 23: 139-142, 2003) • HEPATIC • H1 acute, fulminant • H2 chronic • NEUROPSYCHIATRIC • N1 with liver disease, usually chronic • N2 without symptomatic liver disease • NX liver disease not investigated

  19. Psychiatric issues in patients with Wilson disease (Arch. Gen. Psychiatry 46: 1226, 1984) • Prevalence around 20% • More common in adults than in adolescents and children • Depression is the most common problem • Others include bipolar, neuroses, phobias, compulsive behaviors, aggressive behavior, antisocial behavior

  20. Other occasional features of Wilson disease • Calcium bilirubinate gallstones (hemolysis) • Fatty infiltration of the liver • Renal abnormalities • Microscopic hematuria • Proteinuria • Hypophosphatemia due to phosphaturia • Glycosuria • Hypouricemia due to uricosuria • Renal tubular acidosis • Aminoaciduria • Renal stones / nephrocalcinosis

  21. Tests in Wilson disease • No single test is 100% sensitive or specific • Slit lamp exam if K-F rings not visible to naked eye • Present in 50% of hepatic cases • Present in 98% of neuropsychiatric cases • “Sunfower” cataracts in ant. lens (green/gray) • Ceruloplasmin  in 67-80% of hepatic cases (low normal in others due to acute phase reactant) • Serum copper low unless hemolysis • Urine copper high in adults • Hepatic copper > 250 ug/g dry weight with minimal overlap with cholestatic liver diseases such as PBC, PSC • Mutation analysis not widely available, too slow for fulm-inant cases, but useful if mutation in proband is known

  22. THE KAYSER - FLEISCHER CORNEAL RING

  23. Her sister: clinical heterogeneity despite genetic homogeneity ? … patients homozygous for specific alleles (e.g., H1069Q) reveal little correlation between age at onset, clinical features, biochemical parameters, or disease activity. … clinical heterogeneity seen among affected siblings and identical twins supports that additional genetic and environmental factors contribute to the outcome in any given patient. Tao and Gitlin. Hepatology 37: 1241-1247, 2003.

  24. Therapy of Wilson disease • Low Copper diet • liver, kidney, nuts, chocolate, shellfish, and mushrooms • Chelation • Penicillamine [3-mercapto-D valine](+ 50 mg pyridoxine/day) • Trientene • Reduced GI absorption • zinc p.o. induces intestinal metallothionein which prefers Cu to Zn, binds Cu but does not transport it, and is then eventually shed into feces • Chelation plus reduced GI absorption • Ammonium tetrahydromolybdate (experimental); may be safer and better CNS-tolerated than penicillamine • Antioxidants, such as alpha-tocopherol (vitamin E) • Liver Transplantation • Fulminant presentation, mortality without OLT  100% • Severe chronic disease unresponsive to medical therapy

  25. PROS: Fulminant hepatic failure presentation Sister died age 14 of fulminant disease Concomitant neuropsychiatric and renal abnormalities CONS: Many classic features of Wilson disease are lacking in this patient Wilson disease

  26. Classic features of H1 Wilson disease LACKING in this patient • Onset of fulminant liver disease before age 40 and usually much earlier • AST is usually > ALT, often 4:1 • AST and ALT are usually < 1500 • Alkaline phosphatase is usually normal or even low • Disproportionately high serum bilirubin from acute hemolysis

  27. DRUGS: Isoniazid Halothane Sulfonamides Phenytoin Valproic acid Troglitazone Carbamazepine Nefazodone HERBALS: Jin Bu Huan (Anodyne) Chinese herbal teas Chaparral others Some drugs and herbals causing acute liver failure

  28. Carbamazepine and liver damage • Abnormal LFTs, jaundice with cholestatic or hepatocellular pattern have been reported (PDR) • Cases of granulomatous hepatitis and vanishing bile ducts have been reported as well • Some cases are part of immunoallergic reaction, while others are idiosyncratic • Most cases have been in children and the elderly, and some have associated with renal failure • Many case reports with some fatalities

  29. Selective 5-HT2 RA, Non-selective inhibitor of serotonin and norepinephrine re-uptake by nerves Several published reports of hepatotoxicity since 1999, with one case that was re-challenged Severe injury with very high serum transaminases and jaundice Nefazodone and liver damage

  30. Nefazodone hepatotoxicity a, Annals Int Med; b, Med J Australia; c, Dig Dis Sciences [all 1999]

  31. Nefazodone, continued

  32. Histopathology of nefazadone hepatotoxicity • Initial injury in zone 3 (center of lobule) • Collapse of liver architecture, apoptosis, and confluent necrosis which spreads from center of lobule to its periphery • Diffuse hepatocyte ballooning • Lymphocytic infiltration • Nodules surrounded by fibrosis (may progress to cirrhosis) • Canalicular cholestasis with periportal pseudo-glandular formation ( ductular proliferation)

  33. Final list of possibilities • Nefazodone-induce acute liver failure and hepatic encephalopathy • Carbamazepine-induce acute liver failure • Wilson disease with fulminant liver failure • Autoimmune hepatitis • Acute viral hepatitis from HSV, EBV, HCV • Ingestion of a toxin, eg Amanita phalloides • Hepatic replacement with unsuspected cancer

  34. What was the “diagnostic” procedure? • Liver biopsy after FFP, with copper stain and copper content if histologic features compatible with Wilson • NOTE: she should be referred to OLT facility • Slit lamp exam, 24 hr urine copper output • ANA, ASMA, good response to steroids • HCV RNA – unlikely • Hepatic imaging showing hepatic metastatic disease- unlikely

  35. CPC as cinema. It’s show time!

  36. PROS: liver disease occurs in thyrotoxicosis has history of Grave’s refractory to RAI Current TSH is low CONS: liver disease usually not this severe no clinical signs of hyperthyroidism she was taking exogenous thyroid hormone, perhaps in excess also may have sick euthyroid syndrome with low TSH Thyrotoxicosis, with hepatic dysfunction

  37. PROS: has gallstones on US US may miss CBD stones CONS: transaminases too high encephalopathy US shows no dilation of biliary system  urinary urobilinogen Choledocholithiasis

  38. PROS: acute presentation with abnormal liver tests and liver failure CONS: absence of abdominal pain and tenderness no hepatomegaly no ascites no known risk factors Budd-Chiari syndrome

  39. PROS: history of alcoholism fattly change on US CONS: no recent alcohol use blood alcohol negative transaminases too high ALT > AST no hepatomegaly Alcoholic hepatitis

  40. PROS: not currently drinking obese fatty liver on US ALT > AST CONS: liver is not large encephalopathy rare transaminases too high NAFLD / NASH

  41. BILIARY BLOCKAGE BR Blood/RES Liver BR-MG BR-DG X Bile Via blood BR + 2 Gluc bilirubinuria X Intestine Kidney stercoobilinogen Urobilinogen low or absent X Feces acholic

  42. Heme  biliverdin  BR Blood/RES 1 2 3 urobilinogen Liver BR-MG 3 BR-DG Bile portal vein bacteria BR+ 2 Gluc Urobilin (yellow) Intestine bacteria oxidation Kidney UROBILINOGEN stercobilinogen oxidation Feces stercobilin 1, heme oxidase; 2, biliverdin reductase; 3, bilirubin UDP glucuronyltransferase

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