CPC as CinemaCPC as Cinema

• “The Producers”, starring Drs. Troy Wadsworth and Nilam Soni

• “Clueless”, starring Mark Feldman

• “The Sting”, starring Dr. Dale Odell

The Plot:The Plot:45 year old divorcee

with acute delirium

associated with

hepatic disease

(jaundice, abnormal

liver chemistries and

asterixis).

Asterixis (liver flap)Asterixis (liver flap)• Hepatic failure• Respiratory acidosis• Uremia• Cerebrovascular

disease

The SettingThe 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

Her exam findingsHer exam findings

• 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

Laboratory test abnormalitiesLaboratory 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)

High Urine UrobilinogenHigh Urine Urobilinogen

BR Blood/RES

BR-MG Liver

BR-DG Bile

BR + 2 Gluc

Stercobilinogen

Intestine

stercobilin Feces

UrobilinogenKidney

bacteria

LIVER DISEASELIVER DISEASE

X

BR Blood/RES

BR-MG Liver

BR-DG Bile

BR + 2 Gluc

stercoobilinogen

Intestine

stercobilin Feces

UrobilininogenKidney

bacteria

HEMOLYSISHEMOLYSIS

our patient has liver disease, hemolysis, or both

Toxicology studiesToxicology 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

Why this looks likeWhy this looks like acute liver failure 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

Half lives of certain proteins Half lives of certain proteins synthesized in the liversynthesized 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

Systems involved (when consid-Systems involved (when consid-ering her differential diagnosis)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

Causes of acute liver failure in US Causes of acute liver failure in US and other Western nationsand 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

Five factors predicting high mortality Five factors predicting high mortality in patients with fulminant hepatic in patients with fulminant hepatic

failure (non-acetaminophen)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 OLT3 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]

Acute viral hepatitis A-EAcute viral hepatitis A-E

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

Autoimmune hepatitis (AIH)Autoimmune hepatitis (AIH)

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

Wilson diseaseWilson 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

Liver Cell

apical

sinusoidal

Diet Upper GI absorption portal vein

Ctr 1

COPPER

atox 1 chaperone

Golgi network

apoceruloplasmin

ceruloplasmin blood vesicles

? bile

COPPER (unabsorbable)

periphery (His-Cu)

murr 1

ATP7bATP7b WILSON

(Alb-Cu,His-Cu)

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

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

Psychiatric issues in patients with Psychiatric issues in patients with Wilson disease Wilson disease (Arch. Gen. Psychiatry 46: 1226, 1984)(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

Other occasional features Other occasional features of Wilson diseaseof 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

Tests in Wilson diseaseTests 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

THE KAYSER - FLEISCHER CORNEAL RING

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.

Therapy of Wilson diseaseTherapy 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

Wilson diseaseWilson disease

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

Classic features of H1 Wilson Classic features of H1 Wilson disease disease LACKINGLACKING in this patient 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

Some drugs and herbals causing Some drugs and herbals causing acute liver failureacute liver failure

DRUGS:

IsoniazidHalothane

SulfonamidesPhenytoin

Valproic acidTroglitazone

CarbamazepineNefazodone

HERBALS:

Jin Bu Huan (Anodyne)

Chinese herbal teas

Chaparral

others

Carbamazepine and liver damageCarbamazepine 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

Nefazodone and liver damageNefazodone and liver damage

• 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 hepatotoxicityNefazodone hepatotoxicity

case age sex dose/d time co-Rx Dxs

1a 54 F 200 28 wk chlorazepate BP,T3

2a 16 F 400 14 wk

3a 57 F 200 25 wk

4b 27 M 400 ?????

5c 73 F 400 5 wk lorazepam

Our pt 45 F 500 ????? Carbamaze-pine, others

T3 on Rx

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

Nefazodone, Nefazodone, continuedcontinued

Case Signs/ss outcome BR AST/ALT Alb PT, s

1 J,HE Dead 34 1760/ 2040

2.1 29

2 J OLT 23 1296/ 1345

4.3 25

3 J,HE Well 12 955/ 1626 3.0 13

4 N,V Well 3 453/ 1172

5 J,pain Dead 17 1318/ 834 15

Our pt J, HE ????? 6.6 2233/ 3539

3.0 26

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)

Final list of possibilitiesFinal list of possibilities

1) Nefazodone-induce acute liver failure and hepatic encephalopathy

2) Carbamazepine-induce acute liver failure

3) Wilson disease with fulminant liver failure

4) Autoimmune hepatitis

5) Acute viral hepatitis from HSV, EBV, HCV

6) Ingestion of a toxin, eg Amanita phalloides

7) Hepatic replacement with unsuspected cancer

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

CPC as cinema. It’s show time!CPC as cinema. It’s show time!

Thyrotoxicosis,Thyrotoxicosis, with hepatic dysfunction with hepatic dysfunction

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

CholedocholithiasisCholedocholithiasis

PROS:

• has gallstones on US• US may miss CBD

stones

CONS:

• transaminases too high• encephalopathy• US shows no dilation

of biliary system urinary urobilinogen

Budd-Chiari syndromeBudd-Chiari syndrome

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

Alcoholic hepatitisAlcoholic hepatitis

PROS:

• history of alcoholism• fattly change on US

CONS:

• no recent alcohol use• blood alcohol negative• transaminases too high• ALT > AST• no hepatomegaly

NAFLD / NASHNAFLD / NASH

PROS:

• not currently drinking• obese• fatty liver on US• ALT > AST

CONS:

• liver is not large• encephalopathy rare• transaminases too high

BR Blood/RES

BR-MG Liver

BR-DGBile

BR + 2 Gluc

stercoobilinogen

Intestine

acholic Feces

Urobilinogen low or absent

Kidney

BILIARY BLOCKAGEBILIARY BLOCKAGE

X

X

X

Via bloodbilirubinuria

BR Blood/RES

BR-MG Liver

BR-DG Bile

BR + 2 Gluc

stercobilinogen

Intestine

stercobilin Feces

UROBILINOGENKidney

bacteria

Urobilin (yellow)

Heme biliverdin 1 2 3

3

1, heme oxidase; 2, biliverdin reductase; 3, bilirubin UDP glucuronyltransferase

oxidation

oxidation

urobilinogen

bacteriaportalvein