Optimizing treatment and follow-up for acute porphyric patients.

Acute porphyrias are a group of metabolic disorders, characterized by attacks
of abdominal pain and neuropathy. These attacks can be provoked by fasting,
porphyrinogenic drugs, menstrual cycle, alcohol and smoking. Severe attacks can
be accompanied by hypertension, tachycardia, hyponatremia, and neurologic
symptoms, such as pareses, psychosis, epilepsy, coma and can lead to severe
morbidity and even death.

Acute porphyric attacks are caused deminished activity of enzymes involved in
haem-synthesis by steep increases in delta-aminolevulinic acid (ALA) and
porphyrin levels. Attacks can occur in patients with a latent decreased
activity of specific enzymes in the hepatic heme synthesis, namely
porphobilinogen deaminase (acute intermittent porphyria), protoporphyrinogen
oxidase (variegate porphyria), and coproporphyrinogen oxidase (hereditary
coproporphyria).

The acute porphyria's are autosomal dominant disorders and
screening/councilling for family members can be important. This way attacks may
be recognised early and with lifestyle changes might be prevented. About 20% of
patients with acute porphyria has at least one attack during his/her lifetime
and about 5% has frequent recurrent attacks requiring constant therapy and
painkillahs. In families with one type of porphyria there are usually a lot of
different phenotypes, thus far it's unknown what causes this variation in
phenotype.

Besides the chance to get an acute attack patients with porphyria also have a
higher chance to develop long-term complications of the disease: hypertension,
chronical kidney disease and hepatocellular carcinoma. The risk for
hepatocellular carcinoma in this patient group without liver cirrhosis is
comparable with patients suffering of hepatitis C induced liver cirrhosis.

(also see: C1. Protocol, page 12, paragraph 2)
Primary Objective:
Improving risk assessment of acute porphyric attacks and complications in
patients with acute porphyria.

Secondary Objectives:
1. Obtain and describe basic demographics and statistics, such as mortality and
morbidity.
2. Determine disease modifiers for porphyric attacks and complications.
3. Evaluation of current follow-up (FU) for complications and prevention of
attacks.

Main question is: can improved genotyping and improved phenotyping provide a
more accurate risk assessment to predict those at risk of a (life-threatening)
porphyric attack, or at risk for hypertension, RF and HCC

Specific research questions:
1. Is there a historically increased mortality in the pedigrees of acute
porphyria families compared to the Dutch population?
2. Can we predict those at risk for attacks and / or complications?
3. Can we continue with the current FU schedule (half yearly liver ultrasound
in those over age 50 years and earlier with high levels of plasma PBG/ALA).
4. Is the prognosis of HCC found by screening better than diagnosed after
occurrence of symptoms? Can HCC diagnosed by screening be treated
curatively?
5. What is the burden of screening for patients / carriers? Based on quality of
life (QOL) and qualitative assessments.
6. Can the difference in frequency of acute porphyric attacks be explained by
differences in hepatic enzyme activity between patients?
7. Do patients with episodes of acute porphyric attacks have more stress,
higher levels of hair cortisol, compared to asymptomatic cases and controls?

(also see: C1. Protocol, page 13, paragraph 3)
The study comprises two parts:
A retrospective family cohort study and a prospective genotype-phenotype
variation case control study.

Study population for the retrospective part:
The genealogical data of all families with a DNA-confirmed diagnosis.

Study population for the prospective part:
Cases are all identified patients with acute porphyria in the Netherlands.
Controls are non-carrier, sibs and / or unrelated neighbours / friends /
partners of the patients, preferably age matched on a group level.

(also see: C1. Protocol, page 27/28, paragraph 11.4

The burden of our study for porphyric patients will not deviate from standard
care for these patients given inside our hospital, besides the extra time
needed (about 1 hour) that will be spent filling in questionaires. Tests such
as blood pressure measurements, blood/urine sampling and fine needle liver
biopsies are all part of the standard care for porphyric patients and thus
indicate no extra burden. Patients will be included in the study during routine
check-ups so no extra visits are required. The risks of venapuncture are
haematoma and / or infection at the place where blood was drawn.

The controls will be asked to join patients during routine visits since the
controls will be sibs, friends, partners of the patients. They will be informed
about all the aspects of the study by one of the researchers and especially the
risks associated with fine needle biopsy (20G-FNB).

Most studies on complications of biopsy are based on complications rates in
patients with liver disease. Since the livers of our cases and controls are
considered to be non-cirrhotic, we expect lower complication rates in our
study. The risk of a liver biopsy in patients with cirrhosis are post-biopsy
complications such as bleeding or pain. The risk for complications using 16G
needles consists mostly of pain and minor haemorrhage and is 5,6%. There*s a
1.7% risk for severe complications (extended hospital stay, severe haemorrhage
requiring intervention; the risk of death is 0,06%.

Only cases and controls, aged > 18 years and without risk factors for
complications (paragraph 4.3), can choose to participate in the study with or
without the liver 20G-FNB. It's possible for subjects to enter the study
without giving consent to the liver biopsy.