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Metabolism Elective:
Acute intermittent porphyria
Wilson disease
Mark Korson, MD
VMP Genetics, LLC
1. Demonstrate what is involved in a visit to a
genetic or metabolic clinic.
2. Review the nature of some clinical cases that
present to a metabolic disorder.
3. Describe the challenges of a patient and/or
family in living with a metabolic disorder.
OBJECTIVES
© Copyright 2021. VMP Genetics. All rights reserved
QUESTION #1
Which ONE of the following is the most
accurate statement regarding the diagnostic
pattern of test results for Wilson disease?
a) HIGH ceruloplasmin, LOW urine copper
b) LOW ceruloplasmin, HIGH urine copper
c) HIGH cerulplasmin, HIGH urine copper
d) LOW ceruloplasmin, LOW urine copper
© Copyright 2021. VMP Genetics. All rights reserved
QUESTION #2
Which ONE of the following is NOT a reason why
porphyria patients are viewed with suspicion?
a) Patients often seek relief from pain
b) Patients are mostly from minority
populations
c) Patients are mostly female
d) Patients complain of abdominal pain
e) Patients may have psychiatric symptoms
© Copyright 2021. VMP Genetics. All rights reserved
A VISIT TO THE METABOLIC CLINIC (1)
Preparation Review of all relevant medical
records
Intake Medical history, including a thorough
review of systems
Complete family history
Examination Complete
© Copyright 2021. VMP Genetics. All rights reserved
A VISIT TO THE METABOLIC CLINIC (2)
Differential
diagnosis
Metabolic and other genetic etiologies
Non-genetic possibilities
Triage • If looks ill, or if diagnostic testing
indicates urgent status  ED
• If not ill  diagnostic testing (or
discharged?)
Follow-up Counseling / testing as indicated
Counseling Regarding diagnosis +/- testing, prognosis
© Copyright 2021. VMP Genetics. All rights reserved
CLASSIFICATION
Disorders of
intoxication
Metabolic disease
Disorders of
energy metabolism
Disorders of
complex
molecules
© Copyright 2021. VMP Genetics. All rights reserved
CLASSIFICATION
Disorders of
intoxication
Metabolic disease
Disorders of
energy metabolism
Disorders of
complex
molecules
© Copyright 2021. VMP Genetics. All rights reserved
IT’S TIME FOR CLINIC!
First
patient’s
here!
© Copyright 2021. VMP Genetics. All rights reserved
Acute Intermittent Porphyria
© Copyright 2021. VMP Genetics. All rights reserved
ACUTE INTERMITTENT PORPHYRIA
Acute hepatic
porphyrias
Acute intermittent porphyria
Variegate porphyria
Hereditary coproporphyria
ALAD-deficiency porphyria
© Copyright 2021. VMP Genetics. All rights reserved
ACUTE INTERMITTENT PORPHYRIA
Incidence About 1:20,000
Most common of the acutely
presenting (hepatic) porphyrias
Male < Female
Male:Female
After childhood
Age of onset
Autosomal dominant
Inheritance
© Copyright 2021. VMP Genetics. All rights reserved
BIOCHEMISTRY
© Copyright 2021. VMP Genetics. All rights reserved
BIOCHEMISTRY
HEME
BONE MARROW LIVER
© Copyright 2021. VMP Genetics. All rights reserved
BIOCHEMISTRY
GLYCINE SUCCINYL CoA
5-AMINOLEVULINIC
ACID
PORPHOBILINOGEN
5-ALA synthase
© Copyright 2021. VMP Genetics. All rights reserved
BIOCHEMISTRY
GLYCINE SUCCINYL CoA
5-AMINOLEVULINIC
ACID
PORPHOBILINOGEN
Porphobilinogen deaminase
© Copyright 2021. VMP Genetics. All rights reserved
CLINICAL PHENOTYPE
© Copyright 2021. VMP Genetics. All rights reserved
ACUTE ATTACKS
Presentation Acute attacks are the most
common presentation
More chronic presentations also occur
Medications
Hormonal variation
Infections
Nutrition (carbohydrates)
Stress
Alcohol
Triggers
© Copyright 2021. VMP Genetics. All rights reserved
SYMPTOMS
Pain Abdomen > head, arms/legs, chest
Abnormalities in heart rate and
blood pressure
Sweating
Tremors
Disturbed bowel motility + bladder
function
Autonomic
dysfunction
© Copyright 2021. VMP Genetics. All rights reserved
SYMPTOMS
Neuropathy Muscle weakness
Sensory loss, pain
May not follow a specific nerve
distribution
Confusion
Hallucinations
Depression
Anxiety
Psych disturbances
© Copyright 2021. VMP Genetics. All rights reserved
SYMPTOMS
Urine
© Copyright 2021. VMP Genetics. All rights reserved
SYMPTOMS
Urine
© Copyright 2021. VMP Genetics. All rights reserved
WHY ARE THESE PATIENTS
VIEWED WITH SUSPICION?
© Copyright 2021. VMP Genetics. All rights reserved
MassBio
https://www.youtube.com/watch?v=SM6BFzum8yI
Introducing…
Lina
CASE 1 – COLLEGE FRESHMAN W/ SEVERE ABDOMINAL PAIN
© Copyright 2021. VMP Genetics. All rights reserved
DIAGNOSIS
© Copyright 2021. VMP Genetics. All rights reserved
DIAGNOSIS
Testing Urine porphobilinogen*
Urine 5-aminolevulinic acid
Specimens need to be obtained when the
patient is symptomatic
Urine needs to be collected in a light-
protected bottle
Caution
© Copyright 2021. VMP Genetics. All rights reserved
MANAGEMENT
© Copyright 2021. VMP Genetics. All rights reserved
TREATMENT
Carbohydrates Large doses, >300-500 gm/day IV
Suppresses the first step of heme
synthesis, reducing ALA and PBG levels
Hemin
Degrades ALA synthase mRNA in liver cells
 lowers levels of circulating ALA and
PBG
RNA interference
therapy
© Copyright 2021. VMP Genetics. All rights reserved
TREATMENT
Pain management
Correction of electrolytes
Control of nausea and vomiting
Treatment of anxiety, insomnia
Seizure control
Medical support
© Copyright 2021. VMP Genetics. All rights reserved
PREVENTION!
Warning! Be careful about the medications
that are used!
Careful planning Prevention of attacks
Reduce exposure to triggers
© Copyright 2021. VMP Genetics. All rights reserved
AMOXIL (AMOXICILLIN)
DILANTIN (PHENYTOIN)
ETHINORM E (ETHINYL ESTRADIOL)
LEXAPRO (ESCITALOPRAM)
NEMBUTAL (PENTOBARBITAL)
Patients 2
and 3 are
checked in!
© Copyright 2021. VMP Genetics. All rights reserved
WILSON DISEASE
© Copyright 2021. VMP Genetics. All rights reserved
Ferenci + Roberts,
Gastroenterology,
2012
• Jaundice
• Hepatitis / cirrhosis
• Liver failure  death
GI symptoms
WILSON DISEASE
© Copyright 2021. VMP Genetics. All rights reserved
• Jaundice
• Hepatitis / cirrhosis
• Liver failure  death
GI symptoms
WILSON DISEASE
• Kayser-Fleischer rings in the cornea
• Present in 95% with neuro disease,
50% without neuro disease
Eyes
© Copyright 2021. VMP Genetics. All rights reserved
Dysarthria
Movement disorders
• Uncontrolled movements
• Tremors, rigidity
• Poor coordination
Loss of fine motor control
Neurologic
WILSON DISEASE
© Copyright 2021. VMP Genetics. All rights reserved
Neurologic
WILSON DISEASE
Courtesy of SIMD-NAMA
© Copyright 2021. VMP Genetics. All rights reserved
Neurologic
WILSON DISEASE
Hyperintensity
midbrain
putamen
Hyperintensity
caudate,
pallidum,
thalamus
Courtesy of SIMD-NAMA
© Copyright 2021. VMP Genetics. All rights reserved
Depression
Obsessive/compulsive behavior
Aggressive, anti-social behavior
Personality changes, +/- anxiety
Dementia (memory loss, loss of
abstract thinking, decreased
attention span)
Psychiatric
WILSON DISEASE
© Copyright 2021. VMP Genetics. All rights reserved
Hemolytic anemia
Hematologic
WILSON DISEASE
© Copyright 2021. VMP Genetics. All rights reserved
5-35 years of age
Age of onset
ONSET
Liver disease:
• More common in younger
patients
Neurologic disease more common
in older patients
• Most patients have already
active liver disease
Hemolytic anemia (12%)
Presentation
© Copyright 2021. VMP Genetics. All rights reserved
CASE 2 – WILSON - HEPATIC PRESENTATION
Amanda
Barnes-Jewish Hospital
https://www.youtube.com/watch?v=Q-
Z8B92DQDI
CASE 3 – WILSON - NEUROLOGIC PRESENTATION
Emilee
Miles Boyer
https://youtu.be/NLWuegkn17c
Blood:
• CBC
• Liver function tests
Eye examination:
• Kayser-Fleischer rings
CONSIDERING WILSON DISEASE ?
© Copyright 2021. VMP Genetics. All rights reserved
Blood:
• Low ceruloplasmin
• Low total copper
• High free copper
Urine:
• High copper (free)
Liver:
• High copper
DIAGNOSIS
Ferenci + Roberts,
Gastroenterology,
2012
© Copyright 2021. VMP Genetics. All rights reserved
Wilson.EuroASL.JHepatol.2012
DIAGNOSIS
DNA analysis (ATP7B)
Confirmation
© Copyright 2021. VMP Genetics. All rights reserved
PREVALENCE / INHERITANCE
1/30,000
Prevalence
Sardinia (1/10,00)
At risk
Autosomal recessive
Inheritance
© Copyright 2021. VMP Genetics. All rights reserved
Chelation:
• Penicillamine
• Trientine
Remove copper
(Cu)
THERAPY
Oral zinc
Reduce Cu
absorption
Low copper diet
Reduce Cu
intake
Liver transplantation
Replace Cu
metabolism
© Copyright 2021. VMP Genetics. All rights reserved
REFERENCES
• GeneReviews -
https://www.ncbi.nlm.nih.gov/books/NBK1116/
• Inborn Metabolic Diseases, 6th Edition.
Saudubray JM, et al. Springer, 2016
• Vademecum Metabolicum. Online app - eVM
© Copyright 2021. VMP Genetics. All rights reserved
QUESTION #1
Which ONE of the following is the most
accurate statement regarding the diagnostic
pattern of test results for Wilson disease?
a) HIGH ceruloplasmin, LOW urine copper
b) LOW ceruloplasmin, HIGH urine copper
c) HIGH cerulplasmin, HIGH urine copper
d) LOW ceruloplasmin, LOW urine copper
© Copyright 2021. VMP Genetics. All rights reserved
QUESTION #1
Which ONE of the following is the most
accurate statement regarding the diagnostic
pattern of test results for Wilson disease?
a) HIGH ceruloplasmin, LOW urine copper
b) LOW ceruloplasmin, HIGH urine copper
c) HIGH cerulplasmin, HIGH urine copper
d) LOW ceruloplasmin, LOW urine copper
© Copyright 2021. VMP Genetics. All rights reserved
QUESTION #2
Which ONE of the following is NOT a reason why
porphyria patients are viewed with suspicion?
a) Patients often seek relief from pain
b) Patients are mostly from minority
populations
c) Patients are mostly female
d) Patients complain of abdominal pain
e) Patients may have psychiatric symptoms
© Copyright 2021. VMP Genetics. All rights reserved
QUESTION #2
Which ONE of the following is NOT a reason why
porphyria patients are viewed with suspicion?
a) Patients often seek relief from pain
b) Patients are mostly from minority
populations
c) Patients are mostly female
d) Patients complain of abdominal pain
e) Patients may have psychiatric symptoms
© Copyright 2021. VMP Genetics. All rights reserved
Questions?
Call Genetics!
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Porphyria & Wilson's Disease

Editor's Notes

  1. This classification system was devised by Dr. Jean Marie Saudubray. Metabolic diseases fall into 3 categories - disorders of intoxication, disorders of energy production or metabolism, and defects of complex molecules.
  2. Acutely presenting, or neurovisceral porphyrias. This is in contrast with the cutaneous porphyrias associated with skin manifestations The mode of inheritance is autosomal dominant with variable penetrance
  3. Acutely presenting, or neurovisceral porphyrias. This is in contrast with the cutaneous porphyrias associated with skin manifestations The mode of inheritance is autosomal dominant with variable penetrance
  4. The porphyrias are disorders in the synthesis of heme. Heme is actively produced predominantly in the bone marrow and the liver Bone marrow – used for hemoglobin synthesis Liver – used for production and activation of the cytochrome P450 system, among other important biological pathways If a drug is ingested/used that requires the cytochrome P-450 system for its metabolism, then the system is stimulated which increases flux through the pathway This can be problematic if there is a defect in the pathway. Let’s look more closely….
  5. Those factors that activate the cytochrome P450 enzymes, triggers of a crisis, induce the first enzyme in the pathway, 5-ALA synthase, increasing flux through the pathway,
  6. In acute intermittent porphyria, a deficiency of porphobilinogen deaminase becomes the rate-limiting step and causes elevations in the proximal metabolites – porphobilinogen and 5-aminolevulinic acid – which cause intoxication. These are also the lab metabolites to look for when making a diagnosis
  7. There are several triggers for acute porphyria: Medications Hormonal variation, especially menstrual periods Infections Nutrition, although it is not so much the types of foods but the carbohydrate content, meaning a low intake of carbs Stress Alcohol
  8. The most disturbing of the symptoms that occur in porphyria is the pain. Pain can be excruciating, searing or burning, or sometimes crampy. It is most commonly located in the abdomen but the exam is not necessarily indicative of an acute belly. This can lead to multiple exploratory surgeries that result in no clear cause for the pain. There can be associated nausea or vomiting Notably though, there is usually no fever or significant elevation in the white blood cell count But pain can be described elsewhere as well, in the chest, the head, in the limbs There are also signs of autonomic dysfunction Examples Disturbed bowel motility, diarrhea or constipation, and impaired bladder function
  9. Muscle weakness often starts in the upper extremities but can progress to all limbs and even to the chest Sensory manifestations can present as a painful neuropathy, or as a loss of sensation Deep tendon reflexes can be diminished in severe crises The findings do not necessarily follow a specific nerve distribution, confusing a treating physician The psychological findings include confusion, hallucinations, depression and/or anxiety, and can result from the intoxication itself, or in part as a response to chronic, severe, unremitting symptoms like pain Given the combination of subjective symptoms like pain, neurologic symptoms that may not follow a defined nerve distribution, and the presence of psychological symptoms, it is easy to understand how clinicians unfamiliar with porphyria might label affected patients incorrectly as having primary psychiatric disease or as patients who are fabricating their symptoms
  10. Urine porphyrin metabolites when exposed to long-wave ultraviolet light become oxidized and emit light with a different wavelength (reddish) light.
  11. Urine porphyrin metabolites when exposed to long-wave ultraviolet light become oxidized and emit light with a different wavelength (reddish) light. “Porphyric marble” sarcophagus from Egypt, now in the Vatican Museum
  12. The diagnosis is made by documenting elevated levels of 5-ALA and PBG Spot testing for porphobilinogen is available for rapid testing 5-aminolevulinic acid measurement is done is a specialized testing laboratory
  13. The approach to treating acute porphyria is to reduce flux through the porphyrin pathway. Hemin can suppress the activity of the first enzyme in the pathway shutting down the synthesis of the intoxicating agents. Carbohydrates as IV dextrose is more readily available and can also do this but it is not as effective as the use of the heme compound. Very large doses of dextrose are generally required. CHO might be particularly helpful alone in very mild attacks, and it is generally used until the heme arginate becomes available Small interfering RNA agents. Via RNA interference, they lead to degradation of aminolevulinate synthase 1 (ALAS1) mRNA in hepatocytes, which in turn lowers elevated liver ALAS1 mRNA levels. This decreases circulating levels of the neurotoxic intermediates aminolevulinic acid (ALA) and porphobilinogen (PBG), both of which are linked to attacks and other manifestations of the acute hepatic porphyrias (AHP).
  14. The approach to treating acute porphyria is to reduce flux through the porphyrin pathway. Hemin can suppress the activity of the first enzyme in the pathway shutting down the synthesis of the intoxicating agents. Carbohydrates as IV dextrose is more readily available and can also do this but it is not as effective as the use of the heme compound. Very large doses of dextrose are generally required. CHO might be particularly helpful alone in very mild attacks, and it is generally used until the heme arginate becomes available
  15. The big caution regarding the treatment of porphyria is prevention. Patients and families need to learn how to prevent attacks by reducing their exposure to trigger agents, like avoiding medications that themselves can trigger or exacerbate a crisis. For example, most of the anti-convulsants are porphyrinogenic. For more information about triggers, and an updated list of drugs that are dangerous for patients with porphyria, seek out a reliable resource like the American Porphyria Foundation website
  16. Schematic depicting effects of phenotypic defects in the Wilson ATPase7B (ATP7B) inside the hepatocyte. Copper (red circle) is taken up from albumin and other carriers in blood by the copper transporter CTR1 (bottom of the screen). In the hepatocyte, copper is stored bound to metallothionein or distributed to specific sites via copper chaperones (only ATOX1 shown here). ATP7B (orange cylinder with arrow) is located in the trans-Golgi network (TGN), where it receives copper from the copper chaperone ATOX1 (green nicked-diamond). At low copper concentrations (when the body needs more copper), the ATP7B participates in the mechanism for incorporating copper into apoceruloplasmin (blue collar) to generate holoceruloplasmin (blue collar plus Cu) also known as just “ceruloplasmin” in blood, but at high copper concentrations (when the body’s supply of copper is high), it expedites the excretion of copper in bile to be excreted into the intestine. Potential phenotypic defects due to lesions in the gene include (1) absence of any intact Wilson ATPase, (2) misfolding of Wilson ATPase leading to its retention in the endoplasmic reticulum, (3) failure to bind to ATOX1 (not shown), and (4) ineffective interaction with other proteins, which directs the intracellular movement of the ATP7B (not shown). Any type of phenotypic defect can result in copper accumulation and toxicity in hepatocytes. Legend: BC, bile canaliculus; Mt, metallothionein; RER, rough endoplasmic reticulum; SER, smooth endoplasmic reticulum; TGN, trans-Golgi network.
  17. --The accumulating copper in the liver cells can irritate and inflame the liver, and can cause a wide range of types of liver disease, including hepatitis and cirrhosis. --Patients can present in liver failure; if untreated, this can proceed to renal failure and death (mortality rate=95%). --6-12% of those referred for emergency liver transplantation have Wilson disease as the underlying diagnosis. --Copper from accumulations in the damaged liver leaks out into the blood stream and deposits elsewhere, causing damage in other organs. --Kayser-Fleischer rings are deposits of copper (beige-yellow in color) at the junction of the cornea and iris.
  18. --The accumulating copper in the liver cells can irritate and inflame the liver, and can cause a wide range of types of liver disease, including hepatitis and cirrhosis. --Patients can present in liver failure; if untreated, this can proceed to renal failure and death (mortality rate=95%). --6-12% of those referred for emergency liver transplantation have Wilson disease as the underlying diagnosis. --Copper from accumulations in the damaged liver leaks out into the blood stream and deposits elsewhere, causing damage in other organs. --Kayser-Fleischer rings are deposits of copper (beige-yellow in color) at the junction of the cornea and iris.
  19. --Copper from accumulations in the damaged liver leaks out into the blood stream and deposits elsewhere, causing damage in other organs. --In brain, the deposits can occur in the deep nuclei, called the basal ganglia, responsible for regulating body movements. Their involvement can result in symptoms similar to Parkinson disease, including tremors and rigidity, and problems with gross and fine motor, such as issues with hand-writing.
  20. --Abnormal MRI of the brain of a Wilson disease patient with movement problems. --The abnormally involved “hyperintensity” regions are highlighted in the next slide, where the copper is deposited and causing active injury.
  21. --The abnormally involved “hyperintensity” regions are highlighted here, where the copper is deposited and causing active injury. --Take notice of the caudate, pallidum and thalamus. These are the “basal ganglia,” deep motor nuclei of the brain.
  22. --In brain, the deposits can also occur in the cerebral cortex, resulting in a loss of cognitive function and/or psychiatric symptoms, such as depression, neurosis, personality changes.
  23. --The copper also damages red blood cells causing them to hemolyze or disintegrate, resulting in anemia.
  24. --There is a broad age range when symptoms appear, but most commonly, onset occurs during the 2nd or 3rd decade of life. --Liver disease/jaundice is the most common presentation in younger patients. --Older patients present more often with neurologic/psychiatric symptoms; in these patients, most patients will have active liver disease if you look for it. --12% of patients present with an anemia picture (hemolytic).
  25. --This patient talks about her dealing with the liver aspects of Wilson disease. --It seems that she presented in liver failure, and that her course advanced quickly after that. Priority for transplantation depends on: >> how advanced the liver disease is (higher priority with advanced disease) >> if the patient is in the hospital (higher priority if admitted) >> if the patient is in an ICU (meaning that you are even sicker). --The video is a bit promotional for Barnes-Jewish Hospital in St. Louis, and she clearly loves her doctors/team.
  26. --This patient presented with the neurologic manifestations of Wilson disease. She was also very depressed; it is not clear if that is part of the disease or due to the fact that she has a severely debilitating chronic disease (or both). --Nothing is mentioned about any liver involvement. --When watching the video, take note of the following neurologic findings, specifically the rigidity/stiffness of her muscles: >> neck muscles (note the way she turns her head or holds it… there may be weakness here as well). >> limb muscles (too straight with extension at the elbows and knees). >> finger muscles (kept fully extended and straight with difficulty in using her fingers easily, like closing her fingers around something). >> facial muscles (her smile or expressions can be excessive or unnatural). --Notice she doesn’t say anything. It could be that her dysarthria is so severe that it as decided that she not talk during the video.
  27. --If suspecting Wilson disease, do the following easy tests: >> Complete blood count – is there anemia? If so, look for evidence of hemolysis. >> Liver function tests (AST and ALT, bilirubin, alkaline phosphatase and GGT, PT, INR and PTT, albumin and total protein), looking at the various types of liver function). --An eye examination.
  28. --Low ceruloplasmin in blood – in Wilson disease (WD), the copper inside liver cells cannot bind with apoceruloplasmin to form holoceruloplasmin (aka ceruloplasmin in hospital tests), so blood ceruloplasmin levels are low. --Low total copper in blood. Total copper=free copper and copper bound to ceruloplasmin. Since ceruloplasmin cannot be made, blood total copper levels are low. --High free copper in blood. Copper leaks out of the damaged liver into the blood so levels there are high. --High urine copper. The elevated free copper in urine leaks out into the urine so levels are high there. --High liver copper. There is a massive accumulation of copper in liver tissue since it can’t get out.
  29. --Note the scoring system for diagnosing a patient with Wilson disease. --Biochemical signs do not necessarily correlate with physical signs. If the patient has few clinical signs, looking at the biochemistry or biopsying the liver for copper stores can confirm the diagnosis. And, of course, molecular analysis can easily confirm the diagnosis as well.
  30. --Obvious.
  31. --Patients with active disease need to be ”decoppered” in which chelating agents actively bind copper internally and help to clear the copper excess; this results in higher urine copper levels. After copper stores are cleared, patients continue taking a chelator on a maintenance dose. --Also, patients should follow a low copper diet, especially around the time they are diagnosed. High copper foods include nuts, shellfish, organ meats (liver, brain), chocolate, mushrooms. --Metallothionein binds copper in cells. Zinc salts (like zinc sulfate) induces the synthesis of metallothionein in cells, including in the enterocytes that absorb nutrients (including copper) from digested food in the gut. The metallothionein binds the copper there. Enterocytes are continuously shed (into the stools) as new cells take over; the excess bound copper is shed with the old enterocytes. --With advanced liver failure, replacement of the liver normalizes liver function and provides new (donor) ATP7B molecules.