the acute porphyrias
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The Acute Porphyrias Düsseldorf, Sept13th 2015
Christer Andersson 2015, prof. Family Medicine University of Umeå, Sweden
Clinical features ���Triggers of the acute attack���Diagnosis ���Late complications
Treatment���Various ���What´s on���Where to get more info
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RÖD URIN
SMÄRTTILLSTÅND
400 nm
PORFYRINER
PORPHYRIA
Porphyrins are compounds that make grass green and blood red/ Hans Fisher 1930
Porphyrins
RED URINE
SYMPTOMS
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Porphyria, The red disease, The family disease GP MD Einar Wallquist
n Always the same uncomfortable feeling for me – What did those patients suffer from – I had no idea…
n Peculiar cases …..Sudden severe abdominal pain or increasing paresis….
n After a few days the attack was over…New attacks… Suspected almost all abdominal causes….
n Her strength declined. The puls rate increased…. Having enough of life she welcomed her death when it one evening came as respiratory paralysis.
1701
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Cytoplasm
HEME BIOSYNTHESIS AND HEREDITARY PORPHYRIAS
Mitochondria
Glycine +SuccinylCoA
HEME
Protoporphyrin
Proto´gen
Fe2+
Copro´gen oxidase HCP
Erythropoietisk protoporfyri, EPP. Debut from infancy. Photosensitivity with skin pain. Risk for severe liver damage
Heme proteins
Heme degradation
Ferrochelatase EPP
ALA PBG
Proto´gen oxidase VP
ALA syntase ALA dehydratase ADP
PBG deaminase AIP
HMB
Uro´gen III syntase CEP
Uro´gen decarboxylase PCT
Uro´gen
1 2
3
4
5
6
7
8
Copro´gen
ALA-dehydratase (ALAD) deficiency porphyria, ADP. Autosomal recessive. Six cases
Acute intermittent porphyria, AIP.Autosomal dominant. Chrom. 11.���Manifest 10-40%. Debut around��� puberty. Abdominal pain, Neuro-psychiatric symptoms. Complications: Hypertension, Renal impairment. Liver cancer.The most common acute porphyria1000 registered cases in Sweden.
Congenital erythropoieticporphyria, CEP.
Porphyria cutanea tarda, PCT.Photosensitivity with blisters and fragile skin. No neurological ���symptoms. 1500 registered cases in Sweden Familiar PCT: Onset from child.Sporadic PCT: Middle age, alcoholSecondary and toxic PCT.
Hereditary coproporphyria, HCP. Autosomal dominant. Limited ���penetrance. Debut from puberty. Symptom like AIP + photo-���sensitivity with blisters and fragile skin. Precipitating factors as in ���AIP. 30 gene carriers registered in Sweden
Variegate porphyria, VP.Autosomal dominant. Chrom. 1.Limited penetranse. Debut from puberty. Symptoms like AIP + photosensitivity with blisters ���and fragile skin.���Precipitating factors as in AIP. ���70 gene carriers registered in Sweden.
X-linked dominant ���Protoporphyria
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Acute intermittent porphyria, AIP
n Inherited metabolic disorder– defect in the heme biosyntetic pathway (mutations)
n Combination of heredity and environment – Drugs n Manifest AIP (10 - 40%).
n Acute attack: • Severe abdominal pain • Muscle pain / paresthesia • Muscle weakness – Paresis • Psychiatric symptoms
n Autonomic, Periferal and Central nervous system n Red urine (gr. porphyros, purpur) n Women in fertil age are most severely affected
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AIP, Important rare disease
n Frequent in certain areas
n Dramatic and severe symptoms – potentially life-threatening attacks
n Hereditary – can be traced
n Prevention and information of utmost importance
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Symptoms during AIP attacks n Autonomic nervous system
n Abdominal pain n ä heart frequency, n Hypertension n Bladder paresis
n CNS n Restless, Anxiety n Depression n Confusion, Hallucination n Hypothalamus
n åSodium levels
n Peripheral nervous system n Pain in Muscles and Back n Muscle weakness, Paresis n Sensory disturbances
n Red urine
n Serious signs:
n Paresis, bulbar paralysis n Confusion n Severe hyponatremia n Respiratory paresis
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Karim Z, et al. Porphyrias: A 2015 update. Clin Res Hepatol Gastroenterol (2015),
Clinical features in various acute porphyrias
AIP: Acute intermittent porphyriaHC: Hereditary coprorphyriaVP: Variegate porphyria
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AIP-NORRLAND STUDY 1995-99
1999-11-01 YF
4 .0 5 . 4
4 .4 4 . 6 7 .4
2 . 2 2 . 5 6 . 3
8 . 9
1 . 3 0 0
6 . 6
102
57 3 . 8
6. 7 3 . 5
5 .5
5 . 9
13
468 patients with AIP diagnosis
356 participants (92%)
30 non-participants
386 ≥ 18 yrs82 Children
MAIP 149 (42%)Mean age 52Men 53 (35%)Women 96 (65%)
LAIP 207 (58%)Mean age 40Men 123 (60%)Women 84 (40%)
Prevalens
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Prevalens of symptoms in 149 patients with Manifest AIP (96 w, 53 m)
0 10 20 30 40 50 60 70 80 90 100
Svår buksmärta
Kräkning
Förstoppning
Huvudvärk
Psykiska symtom
Trötthet
Palpitationer
Muskelvärk
Pareser
Känselnedsättning
%
Abdominal pain + 1-2 other symptoms (90%)Sensory impairment
Paresis
Muscle pain
Palpitations
Psychiatrics
Headache
Constipation
Vomiting
Abdominal pain
Fatigue
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Precipitating factors in149 patients with Manifest AIP (96 women, 53 men)
0 5 10 15 20 25 30 35
Medicin
Fasta
Fysisk stress
Psykisk stress
Alkohol
Arbetsmiljö
Infektion
Graviditet
Menstruation
%
Menstruation
Pregnancy
Infection
Work environment
Alcohol
Stress, psychol.
Stress, physical
Fasting
Drugs
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AIP Attacks……. Women severely affected!
n Manifest AIP: 2/3 women, 1/3 men
n Number of AIP attacks n > 20 attacker: 40% of women
25% of men n Duration
n Usually 3-7 days n > 10 days: 15% of women
2% of men
n Most troublesome age n Women: 15 – 39 yrs ,
max 25-30 yrs (most fertile age) Men: max > 40 yrs
n Hospital care n > 20 times: women 12%
men 6%
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Diagnosis of AIP n Acute attack U-PBG increased n Investigation of
gene carriers n Known AIP family: DNA diagnostics n Unknown AIP family: Urine test for ALA, PBG
Blood test for enzyme analys
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Late complications of AIP
n Chronic impairment (20%)
n Slight sensory or motor neuropathy (15-20%) n Few cases with severe paresis
n Chronic Hypertension MAIP 40% (Odds ratio x 4)
n Renal impairment MAIP 30%
n Liver cancer (HCC) n AIP is a high risk
group for developing HCC (RR 60 folds)
n Screening Ultrasonography from 50 yrs age
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Follow up n Blood pressure n Renal check n Liver (yearly from 50 yrs age) n Attacks, ALA and PBG levels n Other gene carriers in the family? n Patient-focused information
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Cytoplasm
Mechanisms underlying acute attacks in porphyria
Mitochondria
Glycine +SuccinylCoA
HEME
Protoporphyrin
Proto´gen
Fe2+
Copro´gen oxidase HCP
Erythropoietisk protoporfyri, EPP. Debut from infancy. Photosensitivity with skin pain. Risk for severe liver damage
Heme proteins
Heme degradation
Ferrochelatase EPP
ALA PBG
Proto´gen oxidase VP
ALA syntase ALA dehydratase ADP
PBG deaminase AIP
HMB
Uro´gen III syntase CEP
Uro´gen decarboxylase PCT
Uro´gen
1 2
3
4
5
6
7
8
Copro´gen
ALA-dehydratase (ALAD) deficiency porphyria, ADP. Autosomal recessive. Six cases
Acute intermittent porphyria, AIP.Autosomal dominant. Chrom. 11.���Manifest 10-40%. Debut around��� puberty. Abdominal pain, Neuro-psychiatric symptoms. Complications: Hypertension, Renal impairment. Liver cancer.The most common acute porphyria1000 registered cases in Sweden.
Congenital erythropoieticporphyria, CEP.
Porphyria cutanea tarda, PCT.Photosensitivity with blisters and fragile skin. No neurological ���symptoms. 1500 registered cases in Sweden Familiar PCT: Onset from child.Sporadic PCT: Middle age, alcoholSecondary and toxic PCT.
Hereditary coproporphyria, HCP. Autosomal dominant. Limited ���penetrance. Debut from puberty. Symptom like AIP + photo-���sensitivity with blisters and fragile skin. Precipitating factors as in ���AIP. 30 gene carriers registered in Sweden
Variegate porphyria, VP.Autosomal dominant. Chromosome 1.Limited penetranse. Debut from Puberty. Symptom like AIP + photosensitivity with blisters ���and fragile skin.���Precipitating factors as in AIP. ���70 gene carriers registered in Sweden
X-linked dominant ���Protoporphyria
Red Urine
Nerve injury
FastingInfectionsStress
DrugsSex hormonesAlcohol
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Treatment of the acute attack
n Triggering factors Eliminate: drugs, infection n Specific treatment 10% Glucose infusion, 2-3 l/d
Severe cases – Heme arginat Normosang 3 mg/kg/d, 3-4d
n Symptomatic treatment n Nutrition Adequate calorie intake n Pain Opoid –Morphine n Nausea/vomiting Clorpromazine, Ondansetron
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Treatment, cont.
n Constipation Senna, Lactulos, n Hyponatremia Substitution. SIADH? n Psychiatric symptoms Clorpromazine, Haloperidol n Hypertoni Atenolol, Labetalol n Seizures Diazepam, Clonazepam,
Gabapentin
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Treatment of menstrual related attacks and treatments in the future
n Cyclic attacks n GnRH agonister
(chemical castration) with add back
n Future?? n Recombinant PBGD
n Gene therapy
n Livertransplantation
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AIP in Northern Sweden Population-based studies
n Penetrance for various AIP mutations
n Porphyria, women and sex hormones
n Surveillance of Liver cancer
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AIP-NORRLAND STUDY 1995-99
1999-11-01 YF
4 .0 5 . 4
4 .4 4 . 6 7 .4
2 . 2 2 . 5 6 . 3
8 . 9
1 . 3 0 0
6 . 6
102
57 3 . 8
6. 7 3 . 5
5 .5
5 . 9
13
468 patients with AIP diagnosis
356 participants (92%)
30 non-participants
386 ≥ 18 yrs82 Children
MAIP 149 (42%)Mean age52Men 53 (35%)Women 96 (65%)
LAIP 207 (58%)Mean age 40Men 123 (60%)Women 84 (40%)
Prevalens
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Clinical penetrance for three AIP mutations
n First mutation in the AIP gene 1989 n 350-400 various mutations,
40 in Sweden n Different severity of the mutations?
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Three mutations: Manifest-Latent AIP
0 20 40 60 80 100
R173W
W198X
R167W
Manifest AIP Latent AIP%
Total (%) Manifest (%) OR CI (95%) p
24 (6) 3 (13) 1.00
338 (91) 147 (44) 7.92 2.13-29.40 0.002
10 (3) 5 (50) 6.38 0.98-41.59 0.053
Conclusion: Various penetrance for different mutations – ���Attention for late complications
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Female sex hormones and AIP
Aims Disadvantages in AIP? - Use of contraceptive pills - Use of postmenopausal hormon replacement theraphy - Pregnancy
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Female sex hormones play a key role in the clinical expression of AIP
n Symptoms rarely before puberty
n Manifest AIP is more common among women than men (3/2)
n Premenstrual cyclic attacks (30%)
n Fewer attacks after menopaus
n GnRH agonister may ameliorate premenstrual attacks
n Contraceptive pills may provoke attacks
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Contraceptive pills and AIP attacks
Clinical course of AIP in 50 women with manifest AIP and used P-pills (57%)
Provoced any attack: 12 (24%) • First attack : 9 (18%)
Relief of AIP symptoms: 1
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Conclusions, female sex hormones
n 1 of 4 women with manifest AIP reported attacks
associated with their use of oral contraceptives
- Caution still recommended
n Post menopausal sex hormone replacement seldom affects AIP - Can be used
n Pregnancy seldom affects AIP - 10% experienced more attacks but 23% felt more healthy
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Screening for hepatocellular carcinoma in acute intermittent porphyria – a 15-year prospective follow-up in northern Sweden
Innala E, Andersson C. JIM 2010
Primary liver cancer and acute intermittent porphyria
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Results Liver cancer
n 22 patients with AIP Porfyri had liver cancer (men:women 12:10), 73% MAIP
n The yearly incidens of Liver cancer in AIP: 0.8%
n The increased risk (incidence rate ratio) for Liver cancer in AIP:
in total: x 64 men: x 52
women: x 93
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Results Liver cancer – survival
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CONCLUSIONS 1 Acute porphyrias and liver cancer (HCC)
n Increased risk of HCC in acute porphyria gene carriers > 50 yrs of age
n The porphyria specific risk factors are unclear n ALA, Oxidative stress. Attack – defence n Oncogene / Tumor suppressor gene linked to the mutation in
porphyria?
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CONCLUSIONS 2 Acute porphyrias and liver cancer
n Surveillance for HCC in acute porphyria gene carriers enables early diagnosis and potentially curative treatments
n Liver function tests and α-fetoprotein are not useful in surveillance of HCC
n Biochemical and/or clinical relapse of the porphyric condition may be associated with the development of HCC
n Annual surveillance using liver imaging (Ultrasonography) is recommended for gene carriers aged > 50 years - Swedish National Guidelines for Liver Cancer 2011
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Treatment of AIP – What´s on?
n Liver transplantation n Liver cell transplantation
n Enzyme replacement therapy – Recombinant PBGD
n Gene therapy
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Treatment of very severe AIP by liver transplantation. Case The Lancet Febr 28 2004
n Woman 19 yrs n Frequent, not menstrual related attacks,
during 2,5 yrs. 37 hospital admissions, 200 days
n Severe abdominal pain, pain in the legs with peripher paresis, æ Na, Renal impairment
n Aunt died due to AIP at 35 yrs of age
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Liver transplantation as treatment of AIP The Lancet Febr 28 2004
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After liver transplantation Liver Transplant 2007;13
n Follow up 5,5 år: No AIP attacks. Nerve function normal
n U-ALA and U-PBG normal levels
n High Quality of life, children
n Around 20 liver transplantations performed due to AIP, (1 due to VP) 3 cases of double transplantation ie liver and kidney
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Gene therapy in AIP
n Recombinant inert Virus targeted to the liver carrying a normal AIP gene
n I.v. injection – transfecting 20-30% of the liver cells
n Porfyri knock out mice - PBGD enzyme levels in the liver normalized - Symptom reduction - Power for >2 yrs
n Clinical and experimental studies ongoing
n RNA interference (RNAi) n Professor Desnick knows
all about this interesting approach: 1. Treatment of acute attacks 2. Profylax in patients with recurrent attacks
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Where to get more info
International Drug data base for acute porphyria www.drugs-porphyria.org
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Goals in the care of Porphyria
n Understand that the patient has porphyria! n The patient must be understood! n High quality of -
n Prevention – no attacks by mistake!!! n Drugs???
n Control and treatment of Porphyria / Late complications (Blood pressure, Kidney function, Liver cancer surveillance)
n Increased Q of life for patients with Porphyria Patient organisations