Pathophysiology: Toxic Metabolites of Phenylalanine
To understand the pathophysiology of phenylketonuria, show that when phenylalanine accumulates at toxic levels, it transaminates into:
- Phenylpyruvate (aka phenyl ketone); hence, “phenylketonuria” describes the presence of phenylpyruvate, phenylalanine, and two key other derivatives in the urine and blood:
- Phenylacetate which has a distinct “must/mousy odor”.
Phenylalanine Excess / Tyrosine Deficiency
- Thus, overall indicate that in phenylketonuria, there is an:
- Excess of phenylalanine
- Deficiency of tyrosine
So the goal of therapy is to reduce phenylalanine intake and to supplement tyrosine deficiency via the diet. Remember the sparing action of tyrosine on the requirements of phenylalanine
Clinical Presentation of PKU
- Indicate that hypopigmentation (of the skin and iris) is a finding in this disorder (remember: melanin is a derivative of tyrosine and tyrosine is deficient in PKU).
- Neuropsychiatric disorder
- And because the toxic levels of phenylalanine and its derivatives are neurotoxic, this disorder causes tremo r, psychosis, seizures, and cognitive dysfunction.
Clinical Presentation of Pheochromocytoma
- Spontaneous severe anxiety: palpitations, sweating, panic
- Physical Exam Signs
- Tachycardia (Rapid heart rate)
- Hypertension (High blood pressure)
As a simplification…
- We can attribute the agitation and possible psychosis to the surge in Dopamine.
- Norephine & Epinephrine
- The sympathetic nervous system “fight or flight” symptoms relate to the surge in norepinephrine and epinephrine.
- We test for pheochromocytoma in patients with unexplained episodic hypertension (high blood pressure) with blood and urine collection of:
- Catecholamine metabolite levels
- Metanephrine levels
- Specifically, we typically order:
- Urine and plasma free metanephrines
- Urine and plasma free catecholamines
- Urine homovanillic acid (HVA)
- Urine vanillylmandelic acid (VMA)
- The tests are highly sensitive, which leads to false positives. As anticipated, causes of false positives include:
- Sympathetic nervous system agitation (ie, psychophysiological stress)
- Exogenous triggers of catecholamines: pharmaceuticals, tobacco, caffeine, and illicit drugs.
- Pheochromocytomas are black staining tumors (remember this was the color of melanin, another tyrosine derivative, as well) that classically grow out of the medullary layer of the adrenal gland.
- For a better understanding of the difference between the adrenal medulla and the adrenal cortex, see adrenal gland hormone production.
- Paragangliomas are essentially extra-adrenal pheochromocytomas
- They derive from cancerous autonomic nervous system tissue.
- True to the anatomy of the autonomic nervous system – head/neck ANS paragangliomas are parasympathetic whereas thorax and abdominal paragangliomas are sympathetic.
PHARMACOTHERAPEUTICS IN PARKINSON’S DISEASE
Parkinson’s disease (and for that matter, all Parksinonism syndromes) are Dopamine deficiency syndromes within the brain.
- Indicate that the pharmaceutical carbidopa is used to block the decarboxylation of DOPA to dopamine, peripherally, and increase the bioavailability of dopamine centrally (in the central nervous system – where it is intended to treat Parkinson’s disease).
- Dopamine cannot cross the blood brain barrier but DOPA can, so Dopamine is administered systemically as L-DOPA. However, if it were administered without a decarboxylase inhibitor (such as carbidopa) it would be decarboxylated peripherally into Dopamine and patients would simply become nauseated.
- In the presence of a peripheral decarboxylase inhibitor, DOPA is taken up in the CNS and THEN decarboxylated to Dopamine (in the basal ganglia where it serves to replenish the deficient stores of Dopamine). Carbidopa (itself) doesn’t cross the blood brain barrier.
- Levodopa: Dopamine Precursor
- So to treat a patient with Parkinson’s disease, let’s add levodopa as a Dopamine precursor.
- Carbidopa: DOPA decarboxylation Inhibitor
- At the same time, we need to add Carbidopa to block the peripheral DOPA decarboxylation of DOPA – we need to ensure that the levodopa makes it through the systemic circulation and enters the brain, otherwise it will simply act like any catecholamine within the periphery and increase blood pressure and heart rate but fail to impact the central nervous system Dopamine deficiency state.
- Ropinirole & Pramipexole: Dopamine agonists
- We can also add ropinirole or pramipexole, which are Dopamine agonists that optimize the release of Dopamine from the remaining Dopaminergic neurons within the substantia nigra.
- Entacapone: COMT Inhibitor
- We can add entacapone, which is a COMT inhibitor to increase the circulation of the Dopamine that we’ve stimulated or replaced (ie, we can inhibit catecholamine metabolism).
- Selegeline or Rasagaline: MAO-B Inhibitors
- And we can add selegeline or rasagaline, which are MAO-B (specifically) inihibitors which also increase Dopamine but via MAO inhibition (catecholamine metabolism inhibition).
- The B subunit is specific to Dopamine catalysis, whereas the MAO-A enzyme is less specific and also metabolizes norepinephrine and serotonin, thus drugs that inhibit MAO-A are potentially much more hazardous to use.
- Hypermetabolic state that manifests with:
- Weight loss, sweats, fevers, rapid heart rate.
- Skin and hair thinning
- Grave’s Ophthalmopathy
- Ocular protrusion and reddening
- Show alkaptonuria, which we can think of as a melanin-like substance in the urine and joints.
- It occurs from a deficiency in homogentisate 1,2 dioxygenase.
- This results in a build-up of a melanin-like polymer called benzoquinone acetic acid (a product of the oxidation of homogentisic acid), which binds connective tissue and causes dark pigmentation or ochronosis (arthritis).
- Thus, we can think of alkaptonuria as the opposite of albinism + the build-up of acetic acid in the tissues irritates the joints and causes joint pain.
- Children: Dark Urine
- The presenting manifestation in children is typically urine that darkens when it sits for awhile (not common now with disposable diapers). The darkening occurs from the excess homogentisate in the urine (5,000 mg vs 20-30mg (normally).
- Adults: Join Pain
- In adults, the disease presents, typically, from joint pain from the build-up of acetic acid in the tissues, which irritates the joints.
TYROSINEMIA TYPE I
Pathogenesis: fumarylacetoacetate hydrolase deficiency
- Indicate that tyrosinemia type I (aka hereditary tyrosinemia, tyrosinosis) results from fumarylacetoacetate hydrolase deficiency.
Presenting symptom: “cabbage-like odor”
- Indicate that it characteristically causes a “cabbage-like odor” but importantly causes liver and kidney failure, polyneuropathy, and bone dysplasia (rickets), manifesting early-on with diarrhea, vomiting and tyrosine and its metabolites in the urine.
- Also consider that transient tyrosinemia (elevated blood levels of tyrosine) occurs in ~ 10% of newborns, most often due to vitamin C deficiency or immature liver enzymes due to premature birth.