Clinical Pathology Conference 41 year old male with AMS

1
Clinical Pathology Conference41 year old male
with AMS

• Lisa L. Willett, MD
• General Medicine Noon Conference
• March 11, 2008

2
Case Summary

• 41 Hispanic male
• Nausea, vomiting, diarrhea x 4 days while in New
  Orleans
• Somnolence and hypertension 220/118
• Clonidine at OSH
• UAB admission for confusion, combative
• MICU transfer for airway protection

3
Case Summary

• PMH
• HTN (unknown meds)
• metabolic encephalopathy 2003
• B12 and Vit A toxicity
• Overuse of body building supplements and anabolic
  steroids
• SH
• No drugs, alcohol
• Bisexual, UDS administration exotic dancer

4
Case Summary

• 155/85 121 18 AF
• Disoriented and combative
• Enlarged liver (15cm), not distended
• Neuro
• PERRLA
• Disoriented, unable to follow commands or answer
  questions
• Noted to move all extremities

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Disgression 1The Neuro Exam (or lack thereof)

• Metabolic or structural dysfunction?
• Level of consciousness
• Glasgow coma scale
• Vocalization, eye opening, limb movement
• Motor
• Muscle tone, asymmetries in movement
• Purposely movements (pushing examiner away)
• Reflexes
• Asterixis, myotonic twitches, DTRs, corneal

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Case Summary

• Chem 7
• AG 7
• Ca 8.3
• WBC 9.3 (normal diff)
• Hct 44
• Plt 142
• UDS, UA
• TSH
• Tylenol, salicylate, ETOH

• CK 995 (MB 6.2)
• INR 1.63
• PTT 35
• AST 66
• Alk phos 60, GGT 15
• TBili 1.4
• NH4 148 ? 753

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Clinical deterioration

• CT head diffuse edema
• EEG diffuse encephalopathy
• Dilated, unresponsive pupils
• MRI brainstem herniation
• ICP 55-65 mmHg (nl lt15), mannitol
• Dialysis, phenylacetate/benzoate
• Died hospital day 4

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Case Highlights

• Acute illness
• AMS diffuse encephalopathy
• New Orleans
• GI symptoms
• Hypertension
• Elevated CK and hyperammonemia
• relatively normal LFTs
• Increased intracranial pressure

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My goals for discussion

• Very rare illness
• We may never see a case of this again
• Important implications for common conditions that
  we treat
• Understand something complicated
• Opportunity to learn something new

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Case Highlights

• Acute illness
• AMS diffuse encephalopathy
• New Orleans
• GI symptoms
• Hypertension
• Elevated CK and Hyperammonemia
• relatively normal LFTs
• Increased intracranial pressure

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Digression 2The risks of a weekend in New
Orleans?

• Pat OBrians Hurricane
• Harrahs
• Bourbon street
• Raw oysters

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Digression 2The risks of a weekend in New
Orleans?

• Pancreatitis
• Alcoholic hepatitis
• Afib, holiday heart
• Hepatitis A, B, C
• Acute HIV
• EBV, CMV
• And more

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Hepatitis A

• Fecal oral route of infection
• Bisexual, food ingestions
• Lower socioeconomic areas, poor hygiene
• Incubation 30 days (15-49 days)
• Self limiting
• Rarely fulminant hepatic failure (0.3)
• underlying liver disease

Fiore, Hepatitis A Transmitted by Food, CID
200438705-15
14
Risk factors among persons with Hepatitis A in US
1990-2000
Viral Hepatitis Surveillance Program, CDC
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Foodborne outbreaks

• Food handler or caterer
• Sandwiches, salads, baked goods
• Produce
• Frozen strawberries, lettuce, green onions
• Shellfish (clams, oysters)
• No outbreaks in US in recent history (1973)
• 3 cases in TN from raw oysters in 2005
• 12 cases in Arizona in 2007

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Clinical Presentation of Hepatitis A

• Fatigue, nausea, vomiting, anorexia, RUQ pain,
  fever
• Dark urine, acholic stools, pruritis
• Jaundice and hepatomegaly
• Splenomegaly, LAD, rash, arthritis,
  leukoctyoclastic vasculitis
• AST/ALT gt 1000 IU/dL, elevated bilirubin
  (gt10mg/dL), alk phos

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Hepatitis B

• Acute
• Subclinical (70)
• Icteric (30)
• Fulminant (0.1 to 0.5)
• Chronic
• Asymptomatic carrier
• Chronic infection

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Hepatitis B

• Sexual contact or percutaneous transmission
• Incubation 1 to 4 months
• Anorexia, nausea, jaundice, RUQ pain, fatigue
• ALT/AST 1000-2000 IU/L
• Protime best indicator of prognosis

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Hepatitis C, HIV, other viral Hepatitis

• Same story
• Could have..
• But not the right clinical picture

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Case Highlights

• Acute illness
• AMS diffuse encephalopathy
• New Orleans
• GI symptoms
• Hypertension
• Elevated CK and Hyperammonemia
• relatively normal LFTs
• Increased intracranial pressure

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Where Does Ammonia Come From?
-Byproduct of protein digestion -Bacterial
metabolism
Urea Cycle ? Urea
Seizures Exercise
From glutamine in proximal tubule
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What happens with liver failureor urea cycle
dysfunction?

• Kidneys
• Stop producing ammonia
• Increase urinary excretion
• Skeletal muscle ? Glutamine
• Brain ? Glutamine

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Ammonia ? GlutamineBad for the Brain

• Toxic to astrocytes and neurons
• Lose glutamate receptors
• ? cerebral blood flow
• Autoregulation lost
• Seizures
• Cerebral edema
• Intracranial hypertension

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Causes of Hyperammonemia

• Increased production
• Infection
• Urease producing bacteria (Proteus, Klebsiella)
• Protein load
• Increased catabolism
• Exercise, seizures
• Trauma, burns
• Steroids
• Chemotherapy
• Starvation
• Gastric bypass
• GI hemorrhage
• TPN
• Cancers

• Decreased elimination
• Liver failure
• Cirrhosis (portosystemic shunt)
• Fulminant failure
• Drugs
• Valproate
• Carbamazepine
• Rifabutin
• Inborn error of metabolism
• Urea cycle defect (amino acid metabolism)
• Carnitine deficiency (fatty acid metabolism)

Limketkai, JGIM 2008 23210
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Causes of Hyperammonemia

• Fulminant Hepatitis and Cirrhosis
• Infection
• Valproate
• Malignancy
• Urea cycle disorders

Weng, Am J Emerg Med 200422105-107 Volpato,
Aging Clinic Experi Res 2007 506
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Hyperammonemia Valproate

• Valproate causes liver problems
• Can cause hyperammonemia with normal liver
  function
• Consider patient on valproate,
• post-ictal, lethargy and ataxia
• Not dose-dependent
• Stop valproate, Rx ammonia level

Weng, Am J Emerg Med 200422105-107
27
Hyperammonemia Malignancy

• Rare, but often fatal
• Abrupt mental status change with markedly
  elevated ammonia without liver disease
• Neutropenic phase after cytoreductive therapy or
  BMT
• Multiple myeloma
• Solid organ malignancies with 5 FU

Nott, Leukemia and Lymphoma 200748(9)1702-11 Wen
g, Am J Emerg Med 200422105-107
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Causes of Hyperammonemia

• Fulminant Hepatitis
• Cirrhosis
• Infection
• Valproate
• Malignancy
• Urea cycle disorders

Weng, Am J Emerg Med 200422105-107 Volpato,
Aging Clinic Experi Res 2007 506
29
www.sickkids.ca/HowellLab/images/ureacycle.gif
30
Urea Cycle Disorders

• Carbamyl phosphate synthetase I (CPSI) deficiency
  
• Ornithine transcarbamylase (OTC) deficiency
• Argininosuccinate synthetase (ASS) deficiency
  (classic citrullinemia, type I citrullinemia)
• Argininosuccinate lyase deficiency (ASL)
• N-acetyl glutamate synthetase (NAGS) deficiency
• Arginase deficiency

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Ornithine transcarbamylase (OTC) deficiency

• OTC is a mitochondrial-matrix enzyme
• Catalyzes conversion of ornithine and carbamyl
  phosphate to cirtulline
• 2nd step of urea cycle

Weng, Am J Emerg Med 200422105-107
32
www.sickkids.ca/HowellLab/images/ureacycle.gif
33
Ornithine transcarbamylase (OTC) deficiency

• OTC gene enormous variation
• Over 340 mutations
• X-linked inborn error of metabolism
• Neonatal males (18200 live births)
• Coma, neurologic impairment, fatal in days
• Females (170 carrier ratio)
• Wide phenotypic variation
• Like males, or asymptomatic

Weng, Am J Emerg Med 200422105-107
34
Late-Onset OTC deficiency

• Unrecognized and fatal
• Oldest reported cases
• 58 year old male
• 61 year old female
• Theory mutation determines an enzyme with
  residual activity
• relatively easy to treat once diagnosis is made

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OTC deficiency unmasked

• Infection (pharyngitis, otitis media)
• Steroids
• GI bleed
• Total parenteral nutrition
• Surgery

Atiq, J Clin Gastroenterol 200842213-14 Lein,
Arch Neurol 2007641777-79
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Clinical Course

• Acute onset mental status changes
• Somnolence ? irritability / agitation
• No focal neurological deficits
• Normal labs, except NH4 gt 150 umol/L
• Cerebral edema, coma, herniation
• Arterial ammonia gt 200 umol/L

Atiq, J Clin Gastroenterol 200842213-14 Clay,
Chest 2007132(4) Lein, Arch Neurol
2007641777-79
37
Treatment

• ICH (controversial)
• Hypothermia
• Mannitol
• N-acetylcysteine
• Indomethacin
• Propofol
• Dilantin for subclinical seizures (40)
• ?CK?

Clay, Chest 2007132(4) Enns, NEJM
20073562282-92
38
Treatment

• ICH (controversial)
• Hypothermia
• Mannitol
• N-acetylcysteine
• Indomethacin
• Propofol
• Dilantin for subclinical seizures (40)
• ?CK?

• Hyperammonemia
• Lactulose
• Neomycin
• Nutritional support
• Dextrose, lipids
• Stop protein intake
• Dialysis
• Phenylacetate/benzoate

Clay, Chest 2007132(4) Enns, NEJM
20073562282-92
39
Case Highlights

• Acute illness
• AMS diffuse encephalopathy
• New Orleans
• GI symptoms
• Hypertension
• Elevated CK and Hyperammonemia
• relatively normal LFTs
• Increased intracranial pressure

40
Diagnosis OTC deficiency

• Hyperammonemia from OTC deficiency presenting as
  late-onset urea cycle disorder
• Stress from New Orleans behavior or infection
• Gastroenteritis, or worse
• Increased protein load

41
Case Highlights

• Acute illness
• AMS diffuse encephalopathy
• New Orleans
• GI symptoms
• Hypertension
• Elevated CK and Hyperammonemia
• relatively normal LFTs
• Increased intracranial pressure

42
Case Highlights

• Acute illness
• AMS diffuse encephalopathy
• New Orleans
• GI symptoms
• Hypertension
• Elevated CK and Hyperammonemia
• relatively normal LFTs
• Increased intracranial pressure

43
Diagnosis OTC deficiency

• Tragic that 2003 illness was misdiagnosed
• Liver biopsy or genetic studies
• Family testing and counseling

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Pearls

• Think of hyperammonemia in patients other than
  liver failure
• Acute mental status changes
• Cancer patients (5FU or chemo, heme malignancies)
• Valproate
• Metabolic encephalopathy
• After infection, surgery, GI bleed, steroids