Inborn Errors of Metabolism in the Acutely Ill Adult: Recognizing Late Decompensation of Lifelong Genetic Disorders

Dr Neeraj Manikath , claude.ai

Abstract

Inborn errors of metabolism (IEMs), traditionally considered pediatric diseases, increasingly present in adulthood with life-threatening metabolic crises. These rare disorders pose significant diagnostic challenges, as they mimic common acute illnesses with non-specific symptoms including encephalopathy, metabolic acidosis, and multiorgan failure. The key to diagnosis lies in maintaining a high index of suspicion and obtaining critical metabolic studies during the acute presentation. This review provides a practical approach to recognizing and managing IEMs in critically ill adults, focusing on urea cycle disorders, organic acidemias, fatty acid oxidation defects, and acute porphyrias.

Introduction

The emergency department physician's nightmare: a previously healthy 25-year-old presents with altered mental status, profound metabolic acidosis, and no clear precipitant. Standard sepsis protocols fail to improve the patient's condition. Hours later, ammonia levels return at 450 μmol/L—but liver function tests are normal. This clinical vignette represents the diagnostic challenge of adult-onset IEM crises.

While most IEMs manifest in infancy or childhood, milder variants with residual enzyme activity can remain clinically silent for decades until physiologic stressors unmask the underlying defect. The incidence of symptomatic adult presentations is estimated at 1:2,500 to 1:5,000, though likely underdiagnosed due to limited awareness and diagnostic difficulty.

Pearl #1: Think IEM when severe metabolic derangement seems disproportionate to the apparent clinical trigger (e.g., routine viral illness, minor surgery, or dietary change).

Why Diagnosis Is So Challenging

The Perfect Diagnostic Storm

Rarity breeds unfamiliarity: Most internists encounter fewer than 1-2 cases in their entire career
Phenotypic masquerade: Symptoms overlap with common conditions (sepsis, drug toxicity, psychiatric emergencies)
Time-critical diagnosis: Many metabolic assays require days to weeks for results, yet treatment decisions must be made within hours
Sample requirements: Specific collection methods, timing, and handling are crucial
Non-specific initial laboratories: Routine tests often show only secondary effects

Oyster #1: The "normal" patient history is the red flag. When a patient with no significant past medical history presents with catastrophic illness, consider IEM. Many patients have subtle histories of food aversions (instinctively avoiding dietary triggers) or unexplained episodes during childhood.

The "Metabolic Storm" Workup: Essential First Steps

When IEM is suspected, time is brain (and liver, and kidney). The following panel should be obtained during the acute crisis, as many abnormalities normalize with treatment or metabolic recovery:

Critical Immediate Tests

Blood Studies (EDTA and heparinized tubes):

Ammonia (ice immediately, analyze within 15 minutes)
Lactate and pyruvate (calculate L:P ratio; >20:1 suggests mitochondrial disorder)
Plasma amino acids (fasting state preferred but not mandatory in crisis)
Acylcarnitine profile
Blood gas with anion gap calculation
Glucose, electrolytes (particularly sodium), beta-hydroxybutyrate

Urine Studies (50 mL, frozen immediately):

Urine organic acids (gold standard for organic acidemias)
Urine porphobilinogen and porphyrins
Ketones
Reducing substances

Standard Adjuncts:

Complete metabolic panel, liver function tests
Complete blood count with differential
Creatine kinase
Coagulation studies

Hack #1: Create a pre-labeled "Metabolic Crisis Kit" in your emergency department with appropriate tubes, labels, and a checklist. Include the biochemical genetics laboratory phone number. Minutes matter.

Hack #2: Take extra tubes of blood and urine and freeze them immediately. If you don't send them initially but later suspect IEM, you'll have appropriately collected samples from the metabolic crisis.

Urea Cycle Disorders: The Great Imitator

Clinical Presentation

Urea cycle disorders (UCDs) represent a group of enzymatic defects preventing the conversion of toxic ammonia to urea. While ornithine transcarbamylase (OTC) deficiency is most common, all UCDs share a similar clinical picture:

Classic Triad:

Hyperammonemic encephalopathy
Respiratory alkalosis (ammonia stimulates respiratory center)
Normal or near-normal liver function

Spectrum of Encephalopathy:

Early: Headache, nausea, vomiting, confusion
Moderate: Combativeness, bizarre behavior (often misdiagnosed as primary psychiatric disorder)
Severe: Obtundation, posturing, cerebral edema, herniation

Pearl #2: The degree of hyperammonemia correlates with prognosis. Levels >200 μmol/L (normal <35) indicate severe risk; >500 μmol/L is a medical emergency with high mortality without aggressive intervention.

Diagnostic Features

Laboratory hallmarks:

Marked hyperammonemia (often >200 μmol/L)
Normal bilirubin, transaminases, and INR (distinguishes from hepatic encephalopathy)
Respiratory alkalosis initially, progressing to mixed acid-base disorder
Low BUN (paradoxically, despite elevated ammonia)
Plasma amino acids: elevated glutamine and alanine, low citrulline and arginine (pattern varies by specific enzyme deficiency)

Oyster #2: Always check ammonia in unexplained encephalopathy, even with normal liver tests. Standard hepatic encephalopathy only occurs with significant liver dysfunction—if ammonia is elevated but liver function is intact, think UCD.

Metabolic Triggers in Adults

Understanding triggers is crucial for prevention and patient education:

Catabolic stress: Infection, surgery, trauma, prolonged fasting
High protein intake: Bodybuilding supplements, high-protein diets
Medications: Valproic acid, corticosteroids, chemotherapy
Postpartum period: Dramatic presentation in heterozygous OTC females
Alcohol binge: Associated catabolism and dehydration

Emergency Management

Treatment must begin before confirmatory testing returns:

Stop protein intake immediately (zero protein for 24-48 hours)
High-dose dextrose: 10% dextrose at 1.5-2x maintenance to suppress catabolism
Nitrogen scavengers:
- Sodium benzoate 250 mg/kg loading dose over 90 minutes, then 250 mg/kg/day
- Sodium phenylacetate (or phenylbutyrate) 250 mg/kg loading, then 250 mg/kg/day
L-arginine: 600 mg/kg loading over 90 minutes, then 600 mg/kg/day (except in arginase deficiency)
Hemodialysis: Most effective ammonia clearance if >300-400 μmol/L or deteriorating encephalopathy
Avoid: Valproic acid, haloperidol (can worsen hyperammonemia)

Pearl #3: Hemodialysis, not CRRT. Intermittent hemodialysis removes ammonia 10x faster than continuous renal replacement therapy. In hyperammonemic crisis, use high-flow hemodialysis with frequent monitoring.

Organic Acidemias: The Acidotic Catastrophe

Clinical Overview

Organic acidemias result from defects in amino acid catabolism, leading to accumulation of toxic organic acids. The three most common are:

Methylmalonic acidemia (MMA)
Propionic acidemia (PA)
Isovaleric acidemia (IVA)

The Diagnostic Clue: Profound AGMA + Ketosis

Classic Presentation:

Severe anion gap metabolic acidosis (AG often >30)
Marked ketonuria and ketonemia
Vomiting, altered mental status, potential seizures
Hyperammonemia (though usually less severe than UCDs, typically <200 μmol/L)
Pancytopenia (particularly thrombocytopenia and neutropenia)
Hyperglycemia or hypoglycemia

Pearl #4: When you see profound metabolic acidosis with ketosis AND hyperammonemia together, think organic acidemia. This combination rarely occurs in common conditions like diabetic ketoacidosis.

Distinguishing Features

Methylmalonic Acidemia:

May have chronic kidney disease (tubulointerstitial nephritis)
Elevated methylmalonic acid in urine organic acids (diagnostic)
Check B12 levels (cofactor for methylmalonyl-CoA mutase)
Some cases respond to high-dose hydroxocobalamin

Propionic Acidemia:

Particularly severe hyperammonemia
Cardiac dysfunction (cardiomyopathy, QTc prolongation)
Characteristic "sweaty feet" odor (isovaleric acid)
Elevated propionic acid and 3-hydroxypropionate

Oyster #3: The urine "smells like sweaty feet" or "cat urine"—this is isovaleric acid. While subjective, several case reports document this clinical sign leading to diagnosis.

Triggers and Management

Common precipitants: Infection, excessive protein intake, surgery, dehydration

Emergency treatment principles:

Aggressive fluid resuscitation: Correct dehydration and enhance organic acid excretion
Sodium bicarbonate: Target pH >7.2 (organic acids are renally excreted better at alkaline pH)
High-dose glucose: Suppress catabolism and endogenous protein breakdown
L-carnitine: 100 mg/kg IV (binds and enhances excretion of toxic acyl-CoA esters)
Protein restriction: Eliminate for 24-48 hours, then reintroduce cautiously
Metronidazole/neomycin: Reduce gut bacterial production of propionic acid
Dialysis: For severe acidosis (pH <7.0) unresponsive to bicarbonate

Hack #3: In refractory acidosis despite maximal bicarbonate, don't forget carnitine supplementation. Conjugation of toxic organic acids to carnitine facilitates their urinary excretion.

Fatty Acid Oxidation Disorders: The Hypoketotic Hypoglycemia Puzzle

Pathophysiology and Presentation

Fatty acid oxidation disorders (FAODs) impair the body's ability to generate energy from fats during fasting states. Medium-chain acyl-CoA dehydrogenase (MCAD) deficiency is the most common, but long-chain and very-long-chain defects also occur.

The Paradox: Hypoglycemia WITHOUT Ketones

Normal physiology: During fasting, fatty acid oxidation generates ketones as an alternative fuel source. In FAODs, this process fails, resulting in:

Hypoglycemia (no glucose production from glycogen depletion)
Inappropriately low or absent ketones (diagnostic hallmark)
Accumulation of fatty acid metabolites

Clinical Recognition

Classic scenario: Previously well adult develops "flu-like illness," stops eating, then presents with:

Confusion, lethargy, or seizures
Hypoglycemia (often severe, <40 mg/dL)
Elevated transaminases (ALT/AST in the 1000s, mimicking acute hepatitis)
Elevated creatine kinase (rhabdomyolysis)
Hypoketotic or aketotic state
Normal to low ammonia

Pearl #5: The ratio of beta-hydroxybutyrate to free fatty acids is key. In normal ketotic hypoglycemia, this ratio is >0.3. In FAOD, it's <0.3 despite elevated free fatty acids. The body is trying but failing to make ketones.

Diagnostic Testing

Acylcarnitine profile (dried blood spot or plasma): Reveals specific accumulating acyl-CoA species

MCAD: Elevated C8 and C10 acylcarnitines
VLCAD/LCHAD: Elevated C14-C18 acylcarnitines
MADD (multiple acyl-CoA dehydrogenase deficiency): Multiple chain length elevations

Urine organic acids: Dicarboxylic aciduria (adipic, suberic, sebacic acids)

Management Principles

Dextrose infusion: 10% dextrose at high rates (8-10 mg/kg/min) to maintain glucose >100 mg/dL
Avoid fasting: Frequent feeds even when well
Low-fat diet: Emphasize carbohydrates; fat provides minimal usable energy
L-carnitine supplementation: 100-200 mg/kg/day (controversial but often beneficial)
MCT oil (for long-chain FAODs only): Medium-chain triglycerides bypass defective enzymes
Avoid: Prolonged fasting, high-fat/low-carb diets, prolonged anesthesia without glucose

Oyster #4: Adult-onset FAODs may present with exercise intolerance, recurrent rhabdomyolysis, or "idiopathic" cardiomyopathy years before an acute metabolic crisis. Always consider FAOD in young adults with unexplained rhabdomyolysis.

Acute Intermittent Porphyria: The Great Mimic

Why AIP is Missed

Acute intermittent porphyria (AIP) and related acute hepatic porphyrias (hereditary coproporphyria, variegate porphyria) cause recurrent neurovisceral crises that are frequently misdiagnosed as:

Acute abdomen requiring unnecessary surgery
Guillain-Barré syndrome
Primary psychiatric disorder
Hyponatremia workup without considering the underlying cause

The Diagnostic Triad

Severe abdominal pain (colicky, no peritoneal signs)
Neuropsychiatric manifestations (anxiety, confusion, hallucinations, seizures)
Autonomic dysfunction (tachycardia, hypertension, constipation)

Plus: Dark or reddish urine (porphobilinogen polymerizes on standing)

Laboratory Clues

Diagnostic tests:

Urine porphobilinogen (PBG): Markedly elevated during attacks (>5x normal); single best screening test
Urine aminolevulinic acid (ALA): Also elevated
Hyponatremia (SIADH occurs in 40% of attacks)
Mildly elevated transaminases

Pearl #6: The urine turning dark red or brownish after sitting for hours is a classic sign, but it's only present in ~50% of attacks. A normal-colored urine does NOT exclude AIP.

Motor Neuropathy: The Complication

Progressive ascending weakness can develop, mimicking Guillain-Barré:

Begins with proximal muscle weakness
Can progress to quadriplegia and respiratory failure
Areflexia develops
CSF protein is normal (unlike GBS)
EMG shows axonal neuropathy

Oyster #5: If a patient with "acute abdomen" develops ascending paralysis and hyponatremia, stop everything and check urine PBG. Multiple case reports describe patients undergoing exploratory laparotomy before AIP diagnosis.

Common Triggers

Medications: Barbiturates, sulfonamides, rifampin, oral contraceptives, anti-epileptics (many drugs—check porphyria drug database)
Hormonal changes: Menstrual cycle, pregnancy
Fasting or low-calorie diets: Induces heme synthesis upregulation
Alcohol consumption
Stress, infection

Acute Management

Withdraw precipitating factors: Stop all potentially porphyrinogenic drugs
Hemin (panhematin): 3-4 mg/kg/day IV for 4 days (specific treatment; inhibits ALA synthase)
High-carbohydrate intake: 300+ grams/day; 10% dextrose IV if unable to eat (suppresses heme synthesis)
Pain control: Opioids are safe; avoid barbiturates
Treat hyponatremia carefully: SIADH management with fluid restriction; avoid rapid correction
Seizure management: Gabapentin and benzodiazepines are safe; most anticonvulsants are contraindicated

Hack #4: Create a hospital "Porphyria Safety List" of safe vs. unsafe medications. Anesthesia, psychiatry, and surgery teams frequently need this reference. The website www.drugs-porphyria.org provides a comprehensive database.

Building Your Diagnostic Approach: A Practical Algorithm

The "Red Flag" Checklist for IEM in Adults

Consider IEM when ANY of the following are present:

Neurologic Red Flags:

Unexplained encephalopathy with normal liver function
Psychiatric symptoms + systemic illness
Seizures with metabolic derangement

Metabolic Red Flags:

Hyperammonemia without liver failure (UCD)
High anion gap acidosis + ketosis + hyperammonemia (organic acidemia)
Hypoglycemia with inappropriately low ketones (FAOD)
Elevated lactate without tissue hypoperfusion (mitochondrial disorder)

Clinical Context Red Flags:

Previously healthy young adult with catastrophic illness
Recurrent "crises" with common triggers (infection, fasting, high protein)
Food aversions or unusual dietary habits
Family history of unexplained deaths or metabolic disease

The Two-Tier Testing Strategy

Tier 1 - Emergency Department (results within hours):

Ammonia, lactate, glucose
Blood gas with anion gap
Beta-hydroxybutyrate
Electrolytes, BUN, creatinine
Liver function tests
Creatine kinase
Urinalysis with ketones
Urine for PBG (if indicated)

Tier 2 - Specialized Metabolic Testing (send during crisis, results in days-weeks):

Plasma amino acids
Acylcarnitine profile
Urine organic acids
Urine porphyrins
Consider: plasma acylglycines, very long chain fatty acids, transferrin isoelectric focusing

Pearl #7: Don't wait for confirmatory testing to treat. If clinical suspicion is high, initiate empiric therapy. The morbidity of delayed treatment far exceeds the minimal risk of empiric interventions like protein restriction and dextrose infusion.

Long-term Management and Prevention

Once Diagnosed, Now What?

Genetics and metabolic disease consultation: Essential for definitive diagnosis and management
Genetic counseling: For patient and family members
Personalized crisis plan: Written emergency protocol card for patient to carry
Dietary management: Registered dietitian with metabolic expertise
Trigger avoidance: Education on medications, fasting, infections
Medical alert identification: Bracelet or necklace stating diagnosis

The "Sick Day Protocol"

Patients should have written instructions for managing minor illnesses:

For UCDs:

Immediately reduce protein to minimum
Increase calories from carbohydrates
If vomiting/unable to eat: Emergency department for IV dextrose
Never fast >4-6 hours

For Organic Acidemias:

Increase fluids significantly
Reduce protein
Ensure adequate caloric intake
Monitor for acidosis symptoms

For FAODs:

Never skip meals
Increase carbohydrate frequency (every 2-3 hours while awake)
If unable to eat: Emergency department immediately for dextrose infusion
Avoid prolonged exercise during illness

Preoperative Planning

Metabolic patients require special surgical protocols:

No prolonged fasting: Dextrose infusion from midnight until recovery
Stress-dose dextrose during procedure: 8-10 mg/kg/min
Early feeding postoperatively
Avoid hepatotoxic anesthetics
Coordinate with metabolic specialist

Communication with Specialists

When to Call a Metabolic Disease Specialist

Immediate consultation (before results return):

Hyperammonemia >150 μmol/L without obvious liver disease
Severe unexplained metabolic acidosis with ketosis and hyperammonemia
Hypoketotic hypoglycemia with elevated transaminases
Suspected acute porphyria with neurologic complications

Urgent consultation (within 24 hours):

Any confirmed or highly suspected IEM
Abnormal metabolic testing requiring interpretation
Planning dialysis or advanced therapies

Hack #5: Most academic medical centers have a biochemical genetics fellow or attending on call 24/7. Don't hesitate to call. They'd rather discuss a case that turns out to be sepsis than miss a treatable IEM.

Common Pitfalls and How to Avoid Them

Pitfall 1: Assuming Ammonia Elevation Equals Liver Failure

Solution: Always check liver function tests alongside ammonia. Normal LFTs + hyperammonemia = UCD until proven otherwise.

Pitfall 2: Treating Acidosis Without Identifying the Underlying Cause

Solution: Before empirically treating with bicarbonate, check anion gap, ketones, lactate, and ammonia. The pattern guides diagnosis.

Pitfall 3: Missing the Diagnosis Because You Didn't Think of It

Solution: Maintain an "IEM checklist" in your differential for unexplained severe illness in young, previously healthy adults.

Pitfall 4: Delaying Hemodialysis in Severe Hyperammonemia

Solution: Ammonia >300 μmol/L with encephalopathy warrants immediate dialysis consultation. Pharmacologic management alone is insufficient.

Pitfall 5: Sending the Wrong Tests at the Wrong Time

Solution: Use the metabolic crisis kit. Samples obtained after stabilization may be non-diagnostic.

Key Takeaway Messages

Think Zebra When the Horse Acts Weird: IEMs are rare but treatable causes of critical illness in adults. A high index of suspicion saves lives.
The Pattern is the Clue: Hyperammonemia without liver disease, AGMA with ketosis plus hyperammonemia, hypoketotic hypoglycemia, and abdominal pain with neuropathy are diagnostic patterns.
Time is Tissue: Collect the "metabolic storm workup" during the acute crisis. Many abnormalities normalize rapidly with treatment or after the episode resolves.
Treat Before You Know: Empiric therapy (dextrose, protein restriction, specific scavengers) should begin when suspicion is high, before confirmatory testing returns.
Build a Bridge to the Specialists: Early consultation with metabolic disease specialists, even for suspected cases, improves outcomes and diagnostic accuracy.
Educate for Prevention: Once diagnosed, comprehensive patient education on triggers, sick day protocols, and emergency management prevents future crises.

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Author Disclosures: None Acknowledgments: The author thanks the metabolic disease specialists whose clinical wisdom informs this review.