A 20YearOld Disoriented Woman with Garbled Speech

1
A 20-Year-Old Disoriented Woman with Garbled
Speech
Eugene G. Martin, Ph.D - Professor of Pathology
Laboratory Medicine Daphne Ang, M.D. -
Pathology Resident

• Based upon LABORATORY MEDICINE CASEBOOK. An
  introduction to clinical reasoning
• Jana Raskova, MD Professor of Pathology
  Laboratory MedicineStephen Shea, MD
  Professor of Pathology Laboratory
  MedicineFrederick Skvara, MD Associate
  Professor of Pathology Laboratory MedicineNagy
  Mikhail, MD Assistant Professor of Pathology
  Laboratory MedicineUMDNJ-Robert Wood Johnson
  Medical SchoolPiscataway, NJ

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History and Presentation

• 20-year-old female college student, Amy, is
  brought to physicians office because of
  disorientation and garbled speech of several
  hours duration
• Patient admits suicide attempt with a full bottle
  (24 tablets) of 500 mg. Tylenol (acetaminophen)
  earlier that morning
• Father reports she is in good health, but
  depressed following a car accident four months
  previously in which she broke her nose.
• At the time of the accident negative head CT to
  r/o intracranial hemorrhage
• Patient takes no medication, does not smoke or
  drink
• Physical Exam
• Thin (50 kg) female in no acute distress
• Disoriented to time and place
• Remainder of physical exam unremarkable
• Admitted to hospital

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Which of the following will be LEAST useful in
evaluating Amy?

• PT and aPTT
• Blood glucose
• Serum transaminase
• Acetaminophen plasma levels
• Chest X-ray to document pulmonary edema

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Question 1 Learning Response

• Changes in the lung parenchyma or vasculature are
  not feature of early acute acetaminophen
  poisoning. Pulmonary edema is NOT a
  characteristic of acetaminophen poisoning
• All the laboratory tests are important in
  following the evolving patient status
• Acetaminophen levels correlate with the extent of
  hepatic injury
• Transaminase levels, coagulation tests and blood
  glucose will all reflect the severity of the
  hepatic injury

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Upon ADMISSION (8-10 hrs post ingestion) what do
you expect to see?

• Serum transaminases should be through the roof
• One would expect elevated serum amylase and
  lipase
• There should be a significantly prolonged PT and
  aPTT
• Other than an increase in plasma acetaminophen,
  no changes should be apparent
• Profound changes in CBC should be obvious within
  8-10 hrs

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Learning Response

• Ten hours after ingestion of a 10 gram dose of
  acetaminophen there is little evidence of injury.
  
• Plasma acetaminophen will be elevated
• Severe injury to the liver is occurring, but
  downstream markers of the event have not yet
  become abnormal
• Transaminases will climb to very high levels
• Coagulation abnormalities will occur
• Blood glucose levels will reflect the severity of
  the liver injury

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HEMATOLOGY
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CHEMISTRY
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Additional Studies
Coagulation
Electrolytes
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Total CO2

• TCO2 H2CO3 HCO3-
• Not particularly useful EXCEPT when there is a
  CHRONIC acid-base imbalance, such as bicarbonate
  retention secondary to chronically elevated CO2
• Most clinicians rely on HCO3-
• Total CO2 is usually 5 greater than HCO3

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Additional Studies
Toxicology
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Questions

• How is acetaminophen metabolized?
• What organ systems are likely to be injured?
• What are typical signs and symptoms?
• Would you expect to see biochemical markers 8-10
  hrs. after ingesting Tylenol?
• What can be done to minimize the injury?
• Assuming that you can successively treat Tylenol
  poisoning when would there be most evidence of
  hepatic injury?

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Metabolism of Acetaminophen

• Purpose of drug metabolism ? make drugs more
  water soluble permits urinary excretion
• Three separate pathways.
• About 95 of the agent is conjugated by way of
• Glucuronidation -60
• Sulfation 35
• Only 5 is metabolized by the hepatic microsomal
  mixed-function oxidase enzymes, primarily
  cytochrome P-4502E1 (CYP2E1).
• BUT Such oxidation ? the avidly electrophilic
  compound N-acetyl-p-benzoquinoneimine (NAPQI) -
  highly toxic to liver tissues.

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Liver injury
Nontoxic cysteine, mercaptate
(N-acetyl-p-benzoquinoneimine)
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Major Point

• The safety of Tylenol depends upon the
  availability of electron donors such as
  glutathione (GSH) and/or other thiol containing
  substances required to detoxify NAPQI

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Glutathione levels

• Effected by
• Age
• Diet Fasting/malnutrition
• Liver disease
• Gastroenteritis
• Chronic ETOH ingestion
• HIV

• Increased by
• Sulfhydryl compounds
• Eating
• NAC N-acetylcysteine (MUCOMYST)

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Factors Influencing Acetaminophen Toxicity

• Excessive intake of acetaminophen
• Vary among individuals
• Toxicity single ingestion of 250mg/kg or
  gt12g/24hours
• Excessive cytochrome P450 activity due to
  induction by
• Chronic Alcoholism
• Anticonvulsants (Carbamazepine, Phenobarbital,
  Phenytoin)
• Antituberculosis (Isoniazid, Rifampin)
• Decreased capacity for glucuronidation or
  sulfation
• Antibiotics (TMP-SMX), Antiviral (Zidovudine)
  competes with glucuronidation pathways
• Decreased glucuronidation in fasting/malnutrition
• Depletion of glutathione stores due to
  malnutrition or chronic alcohol ingestion

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Human Cytochrome p450 Enzyme Isoforms
Isoform A protein that has the same function as
another protein but which is encoded by a
different gene and may have small differences in
its sequence.

• Example CYP1 family
• Three genes encode
• CYP1A1
• CYP1A2 and
• CYP1B1
• These genes are inducible e.g. smoking induces
  the CYP1 family of enzymes.
• When induction occurs the enzymes capacity to
  metabolize is increased.
• Ubiquitous - found in liver, intestines, lungs,
  kidney, and etc.

19
Why is APAP damaging to kidneys?

• Organ dysfunction results everywhere where local
  oxidative metabolism (via p450) creates NAPQI
  that cannot be detoxified ? direct toxicity
• cytochrome P-450 enzymes produce NAPQI in the
  renal tubules ? NAPQI binds cellular
  macromolecules ? acute tubular necrosis.
• (25 of hepatotoxic cases).

20
Did someone mention ETOH?

• WHY?
• ETOH induces CYP2E1 and glutathione depletion
  occurs ? ?? NAPQI (N-acteyl-p-benzoquinoneimine).
• The unconjugated NAPQI causes hepatic injury.
• Patients with ETOH abuse may have a worse
  prognosis Average mortality 20 with liver
  failure 80.

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Tylenol poisoning SS

• Uptake rapidly absorbed from GI tract peak
  2hrs
• Body as a whole
• sweating
• convulsions
• tenderness, swelling, or pain in the stomach area
  
• tenderness, swelling, or pain in upper abdominal
  area
• Gastrointestinal
• diarrhea
• upset stomach
• appetite loss
• nausea and/or vomiting
• Nervous system
• irritability
• coma
• Note Symptoms may be delayed for 12 or more
  hours after the acetaminophen was swallowed.

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Four Phases of Acetaminophen Poisoning

• Stage 1 - 0 to 24 hours - manifested by nausea,
  anorexia, vomiting and diaphoresis.
  Asymptomatic. (Acetaminophen levels should be
  drawn if suspected)
• Stage 2 - 24 to 72 hours hepatotoxicity and
  nephrotoxicity right upper quadrant pain,
  elevation of transaminases, TB, PT oliguria,
  deterioration of renal function.
• Stage 3 - 72 to 96 hours symptoms of stage I
  plus jaundice centrilobular hepatocellular
  necrosis including hepatic encephalopathy
  (hyperammonemia), bleeding diathesis,
  hypoglycemia, renal failure (ATN) and death.
• Stage 4 - 4 days to 2 weeks - complete resolution
  of hepatic dysfunction occurs if damage in phase
  3 is not irreversible.
• Acetaminophen toxicity early symptoms may be
  subtle, and the onset of hepatotoxicity, the
  major manifestation, is delayed by several days
  following the ingestion. Failure to recognize and
  treat toxicity early results in significant
  morbidity and mortality.

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Chemistry
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Liver Function Tests - HINTS
ABCs ofTransaminase Elevation

• Common bile duct stone
• Condition can simulate acute hepatitis.
• AST and ALT become elevated immediately, but
  elevation of AP and GGT is delayed
• Isolated elevation of GGT level
• This situation may be induced by alcohol and
  aromatic medications, usually with no actual
  liver disease.
• Isolated elevation of AP level (asymptomatic
  patient with normal GGT level)
• Consider bone growth or injury, or primary
  biliary cirrhosis.
• AP level rises in late pregnancy.

http//www.aafp.org/afp/990415ap/2223.html
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Patient AST
http//www.aafp.org/afp/990415ap/2223.html
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HINTS

• Lactate dehydrogenase (LDH) is less specific than
  AST and ALT as a marker of hepatocyte injury.
• In typical viral or toxic liver injury ALTgtAST
• In alcoholic hepatitis AST gt ALT
• The higher the AST-to-ALT ratio, the greater the
  likelihood that alcohol is contributing to the
  abnormal LFTs.

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Liver Function HINTS

• Results from the blockage of bile ducts or from
  a disease that impairs bile formation in the
  liver itself.
• Alkaline phosphotase (AP) and gamma-glutamyltrans
  ferase (GGT) levels typically rise to several
  times the normal level after several days of bile
  duct obstruction or intrahepatic cholestasis.
• The highest liver Alk.P elevations--often greater
  than 1,000 U per L, or more than six times the
  normal value--are found in diffuse infiltrative
  diseases of the liver such as infiltrating tumors
  and fungal infections

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Liver Biopsy (HE x50)

• Liver lobule. The center of the lobule is the
  central vein. Periphery of the lobule is portal
  triads. Functional zones. Zone 1 encircles the
  portal tracts where the oxygenated blood from
  hepatic arteries enters. Zone 3 is located around
  central veins, where oxygenation is poor. Zone 2
  is located in between.

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Liver Biopsy (HE x50)

• Acetaminophen induced centrilobular necrosis
• Highest metabolic activity and furthest from
  periportal blood supply
• Zone 3 greater concentration of CYP2E1
• Hepatocytes around central vein have disappeared
• Inflammatory cells and pigment-laden Kupffer
  cells
• Some sinusoidal congestion is present

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Centrilobular Necrosis Acetaminophen Poisoning
Liver Biopsy (HE x125)

• Ballooning degeneration evident
• Increased number of Kupffer cells with abundant
  lipofuchsin pigment.
• Inflammatory cells including lymphocytes, plasma
  cells, and neutrophils

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Management

• REMOVE what you can of the Tylenol
• Activated charcoal avidly adsorbs
  acetaminophen, reducing its absorption by 50
  90
• DECREASE formation of NAPQI
• Administer N-acetylcysteine (NAC) (MUCOMYST)
• Glutathione-precursor
• Limits formation of NAPQI
• Powerful anti-inflammatory and anti-oxidant
  limits secondary tissue injury
• Has vasodilating effects improving
  microcirculatory blood flow to vital organs

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Case Summary

• Final Diagnosis
• Acetaminophen poisoning
• Centrilobular necrosis of the liver
• Points
• Signs Symptoms are not conclusive
• History is critical
• Elevation of liver enzymes is maximal at 72
  hours. Not obvious on admission.
• Prompt treatment (lt 10 hrs) with Mucomyst
  minimized the damage by providing cysteine for
  glutathione production.? capacity to metabolize
  NAPQI

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A 20 Year Old Disoriented Woman with Garbled
Speech

• Post-Case Questions

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All of the following about NAC (N-acetylcysteine)
(Mucomyst) are correct EXCEPT

• It is most effective when given within 10 hours
  after ingestion of acetaminophen
• Its major therapeutic effect is the prevention
  of absorption of acetaminophen from the stomach
• It provides cysteine for glutathione synthesis
• It help to reduce the severity of liver necrosis
  in acetaminophen poisoning

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Learning Response

• The main therapeutic effect of NAC is in
  providing cysteine for the synthesis of
  glutathione which is rapidly depleted by
  Tylenolol poisoning.
• Glutathione detoxifies the toxic metabolite of
  Tylenolol by binding to it, thus preventing it
  from reacting with essential cellular compoents.
• Mucomyst is most effective when given during the
  first 10 hrs after poisoning.
• NAC has no effect on stomach absorption of Tylenol

37
Which of the following situations will most
clearly predispose to Tylenol hepatic toxicity?

• Liver P-450 ACTIVITY GLUTATHION
• Normal Increased
• Increased Increased
• Decreased Increased
• Increased Decreased
• Decreased Decreased

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Learning Response

• Answer 4 Increased p450 activity combined with
  decreased glutathione stores
• Liver injury will be potentiated by conditions
  that increase formation of the toxic metabolite
  ?? NAPQI (N-acteyl-p-benzoquinoneimine).
• The unconjugated NAPQI causes hepatic injury.
• Increased Glutathione stores are protective

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Laboratory signs of organ damage in acute
acetaminophen poisoning usually reach their peak
at which interval after ingestion?

• 0-4 Hours
• 4-12 Hours
• 12-24 Hours
• 24-48 Hours
• 2 -4 Days

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Learning Response

• During the first 12-24 hours the only abnormal
  result is likely to be the serum drug level
• In the next 24 hours, liver function tests begin
  to become abnormal.
• In the next 2-4 days liver function test
  abnormalities peak

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An acute Tylenol overdose is best known to cause

• Acute Pancreatitis
• Acute Pulmonary Edema
• Cystitis
• Profound myelosuppression
• Acute Liver Failure

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Learning Response

• Acute Tyelenol poisoning leads to acute liver
  failure due to centrilobular liver necerosis. The
  other conditions listed (myelosuppression,
  cystitis, pancreatitits, and pulmonary edema) are
  not features of the acute phase of acetaminophen
  poisoning

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Does phenytoin treatment for epilepsy make things
worse?

• Yes
• No

44
Is it Better or Worse?

• A similar case EXCEPT patient is on

45
Does antiviral (zidovudine) treatment for HIV
make things worse?

• Yes
• No

46
Is it Better or Worse?

• A similar case EXCEPT patient is on

47
Do sulfhydryl compounds for cystinuria make
things worse?

• Yes
• No

48
Is it Better or Worse?

• A similar case EXCEPT patient is on

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Does anorexia make things worse?

• Yes
• No

50
Is it Better or Worse?

• A similar case EXCEPT patient is on

51
Does Antibiotic Rx with TMP/SMZ treatment for UTI
make things worse?

• Yes
• No

52
Is it Better or Worse?

• A similar case EXCEPT patient is on

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Take Home Point

• In Tylenol poisoning it pays for you to know
• What medications a patient is on
• What their physical condition is
• Whether they abuse alcohol or other drugs
• What mechanisms you could potentially stimulate
  to protect the patient!
• You have a short time to make the right move!