Dr sadeghi , MD

Assistant professor of gastroenterology and hepatology

Acute intermittent porphyria is estimated to affect about one in 75 000 people in European countries, apart from in northern Sweden, where, because of a founder effect, it is more frequent (one in 1000).

Acute attacks are very rare before puberty and after menopause, with a peak occurrence within the third decade. They are more common in women than in men.

Most patients have one or a few attacks and then recover fully for the rest of their lives. Less than 10% develop recurrent acute attacks.

Pathophysiology The alteration in enzyme activity is usually due to an

inherited mutation in the gene for that enzyme.

However, in porphyria cutanea tarda (PCT), the most common of the porphyrias, acquired inhibition of the fifth enzyme in the pathway, uroporphyrin decarboxylase (UROD), develops during life, specifically in the liver.

By way of general introduction, the acute porphyrias are rare metabolic disorders caused by 1 of 4 inherited enzymatic defects in normal heme biosynthesis.

The 4 diseases have rather daunting names: acute intermittent porphyria, hereditary coproporphyria, variegate porphyria, and ALA dehydratase-deficiency porphyria.

Those defects may result in an overproduction of heme precursors, especially delta aminolevulinic acid, which we will generally refer to as ALA, and porphobilinogen, or PBG.

Overproduction fortunately doesn't occur in most patients most of the time; only a minority of people suffer these problems.

But when there is marked, uncontrolled overproduction of ALA and PBG due to a marked induction of hepatic ALA synthase, which is the first rate-controlling enzyme in heme synthesis, then there may be accumulation, first in the liver and then in the blood. These are then overexcreted in the urine and the stool.

Heme is made in all tissues, but the bone marrow and liver are the most active organs involved in overall heme synthesis.

The bone marrow accounts for >80 percent of daily heme synthesis ( all of the synthesized heme is utilized as the prosthetic group for hemoglobin).

The liver accounts for most of the rest of overall heme synthesis. In the liver, heme is utilized primarily for the production of the various cytochrome P450 enzymes (CYPs)

People with autosomal-dominant acute porphyrias—acute intermittent porphyria, variegate porphyria, and hereditary coproporphyria—can present with a sudden lifethreatening crisis.

Skin lesions (similar to PCT) never develop in acute intermittent porphyria but are the only clinical manifestation in some patients with variegate porphyria (60% of patients), and rarely (5%) develop in patients with hereditary coprophorphyria.

ACUTE INTERMITTENT PORPHYRIA

Porphyric attacks begin with a prodromic phase including minor behavioural changes such as anxiety, restlessness, and insomnia.

The cardinal manifestation is abdominal pain, although the pain can be in the chest, back, or extremities. Most people with acute attacks present with severe abdominal pain.

Most acute attacks last for no longer than 1 or 2 weeks.

Abdominal pain is the most common symptom in AIP, occurring in 85 to 95 % of patients with acute attacks .

Often it can be pelvic. It is less often upper abdominal, but it can also involve the upper abdomen.

Because the pain and other symptoms are neuropathic rather than inflammatory, abdominal tenderness, rebound, fever, and leukocytosis are usually minimal or absent during an acute attack.

It is usually severe, steady, and poorly localized but is sometimes cramping, and is often accompanied by constipation and signs of ileus such as nausea, vomiting, abdominal distension, and decreased bowel sounds. However, diarrhea and increased bowel sounds are sometimes seen.

In most series, severe constipation, often to the point of obstipation, is present in around 90%-95% of patients, although a small percentage report diarrhea.

Electerolyte disturbnce :

During acute attacks, patients frequently become dehydrated and electrolyte imbalanced.

Hyponatraemia attributable to inappropriate anti diuretic hormone secretion syndrome develops in 40% of cases, and when severe can lead to convulsion and hallucination. Hypomanasemia and hypercalcemia may be seen.

Autonomic nervous system involvement :

The autonomic nervous system is affected in AIP and circulating catecholamine levels are increased .

Tachycardia is the most common physical sign, occurring in approximately 80 percent of attacks, and is often accompanied by hypertension, sweating, restlessness, and tremor.

CNS manifestations:

Seizures in acute attacks can develop because of hyponatraemia or hypomagnesaemia or as a manifestation of porphyria.

Acute attacks can also be life threatening because of severe neurological complications.

Especially with prolonged attacks, it may also involve cranial nerves and lead to bulbar paralysis, respiratory impairment, and death.

Pyramidal signs, cerebellar syndrome, transitory blindness, or consciousness abnormalities (from somnolence to coma) can arise.

Peripheral neuropathy :

Sensory neuropathy is common and presents with pain in the back, chest, and extremities, and may precede the abdominal pain.

Patchy numbness, paresthesias, and dysesthesias may occur.

Sometimes in an acute setting, peripheral motor neuropathy like Guillain-Barré syndrome (an ascending motor paralysis) may be seen.

Onset of a motor neuropathy is often characterised by severe pain and stiffness in the thighs and back, and then loss of tendon reflexes and motor paralysis.

A peripheral motor neuropathy develops early in some attacks, but is more often a later manifestation of a prolonged attack.

Motor weakness usually begins in the proximal muscles, more frequently in the arms than in the legs. Limb paresis, when it occurs, can be very local.

Muscle weakness can progress and lead to tetraplegia, with respiratory and bulbar paralysis and death.

Cerebrospinal fluid is normal in most cases.

Although advanced motor neuropathy with quadriplegia and respiratory paralysis is potentially reversible with appropriate treatment (eg, intravenous hemin), some permanent paralysis may remain

Neuropsychiatric manifestations:

Insomnia is often an early symptom of an attack.

Other neuropsychiatric manifestations (In 20–30% of patients) include anxiety, restlessness, agitation, hallucinations, hysteria, disorientation, delirium, apathy, depression, phobias and altered consciousness, ranging from somnolence to coma.

Occasionally, excretion of red or dark-coloured urine helps physicians with their investigations.

ALA and PBG are colorless

But PBG degrades to form porphobilin, a brownish product →dark urine

Also urinary porphyrine are increased in AIP→reddish –brown urine

The key point is that there are women who, unfortunately, suffer acute attacks of porphyria almost every month, and it is in the mid-cycle, right after ovulation and the formation of the corpus luteum.

It is not at the time of menstruation, unlike so many other symptoms that are cyclical in these women.

The progestins can cause or precipitate porphyrias, so females, during the luteal phase of their menstrual cycle, often will have a precipitation of their symptoms.

Progestrone and testosterone are induce ALAS1 and CYPs. Estrogen have less effect and could be harmful mostly in association with progestrone

If a patient comes in recurrently and we do an initial gastrointestinal workup, specifically endoscopies and some sort of imaging study, and, perhaps, even do some empiric treatment for irritable bowel syndrome without any margin of success, then at that point I need to start considering a porphyria, especially if the symptoms are more intermittent and less chronic in nature.

Examination of urine for excess porphobilinogen is the essential first-line test for patients with a suspected attack of acute porphyria .

The best test is a urine PBG screening test at the time of symptoms . Testing for increased urinary PBG is also highly specific, since a substantial increase in urinary PBG does not occur in medical conditions other than AIP, HCP and VP

Testing for increased urinary PBG is rapid and sensitive, since marked increases are expected in acute porphyrias, especially at the time of an acute attack.

It is is sensitive enough that, were it to be negative, it would completely exclude the diagnosis of acute intermittent porphyria.

Porphobilinogen is not a porphyrin. It is a monopyrrole, not a tetrapyrrole.

However, PBG may not be elevated when the patient with AIP, HCP, or VP is asymptomatic, and is normal in ALA dehydratase porphyria.

Increases in PBG and ALA can persist for prolonged periods between attacks of AIP but fall more rapidly after acute attacks of HCP and VP. Urinary ALA and PBG excretion often remains elevated between frequent exacerbations, and is sometimes elevated in those who have never had symptoms.

A commercially-available semiquantitative kit rapidly and reliably detects increased urinary PBG on a spot urine specimen

During an acute attack of AIP, urinary PBG excretion is generally 20 to 200 mg/day (markedly higher than the normal rate of approximately 0 to 4 mg/day or per gram of creatinine) , with ALA excretion being approximately one-half that amount (normal range 0 to 7 mg/day).

In patients with end-stage renal disease, the diagnosis of acute porphyria can be established by the presence of a marked elevation in plasma PBG.

Measurement of 5-aminolaevulinic acid is not essential to establish the diagnosis but can be helpful for differentiation of the disorder from the rare 5-aminolaevulinic acid dehydratase porphyria.

I should just mention that there is this one very, very rare form of porphyria caused by severe deficiency of the enzyme ALA dehydratase. There have only been 7 or so reported cases in the entire medical literature.

That is the one form of acute porphyria in which there is not an increase in porphobilinogen. The reason is that the site of the block is proximal to the formation of porphobilinogen, so the defect is in the inability to make porphobilinogen.

Urinary PBG and ALA are increased in all three acute hepatic porphyrias (acute intermittent porphyria, hereditary coproporphyria, and variegate porphyria) alththe concentrations are higher and longer lasting in acute intermittent porphyriaough than in the other two types (hereditary coporphyria and variegate porphyria).

If a screening test for increased urinary PBG is negative on a spot urine specimen but the index of

suspicion is high for an acute porphyria, a 24-hour urine collection should be obtained for quantitative assessment of PBG.

Measurement of urinary porphyrins is unhelpful and might be misleading because of frequent and nonspecific coproporphyrinuria in many common disorders (such as chronic liver disease).

There are lots of disorders or conditions that are not porphyria that have mild increases in urinary porphyrins, particularly in coproporphyrin.

There is a long list of drugs and other conditions that can do that, so it is very important not to jump to the diagnosis just because there is a slight abnormality in urinary porphyrins.

Urinary coproporphyrin is usually more elevated in HCP and VP than in AIP.

However, coproporphyrin is the predominant porphyrin in normal urine and is also increased in many medical conditions other than porphyria.

Its urinary excretion increases in liver disease because it is normally partially excreted in bile

Differentiating AIP from other acute porphyrias — Attacks of all four of the acute porphyrias (ie, acute intermittent porphyria, ALA dehydratase porphyria, hereditary coproporphyria, variegate porphyria) are treated in the same manner.

As a result, treatment can be initiated once there is definite laboratory documentation of a substantial increase in urinary or plasma PBG, while further testing, including measurement of porphyrins in plasma, urine, and feces, and erythrocyte PBG deaminase (PBGD) activity is in progress.

Measurements of total plasma and fecal porphyrins, which are normal or only slightly increased in AIP, are recommended to definitively

exclude HCP and VP .

Plasma porphyrins are increased in VP with a characteristic fluorescence peak at neutral pH.

For diagnosis of the type of acute porphyria in the proband, plasma fluorescence emission spectroscopy is a first-line test because a peak at 624–628 nm establishes the diagnosis of variegate porphyria.

However, it does not distinguish acute intermittent porphyria from hereditary coproporhyria, for which the emission peak at 620 nm is usually present for both types.

Fecal porphyrins are normal or minimally increased in AIP but substantially increased in HCP (with a marked predominance of coproporphyrin III) and in VP (with approximately equal increases in coproporphyrin III and protoporphyrin).

Total faecal porphyrin concentration is raised in hereditary coproporphyria, with coproporphyrin as the main component and a ratio of isomer III to isomer I greater than 2.

When present, a 50% decrease of PBG deaminase (PBGD) activity can positively identify acute intermittent porphyria patients.

Although erythrocyte PBGD activity is approximately half-normal in most patients with AIP, this measurement is not definitive for confirming or excluding a diagnosis.

Erythrocyte PBGD measurement is not useful for the initial diagnosis of acute porphyria in ill patients. Its use as a second line test to confirm a diagnosis of AIP and for screening asymptomatic family members is now largely replaced by DNA testing.

Family screening is essential to prevent acute attacks in those with latent disease. DNA analysis to identify the mutation is the gold standard.

For DNA analysis, previous identification of the mutation in an unequivocally affected family member is needed.

Enzyme measurements are reserved for families in which a mutation cannot be identified .

DNA testing — The underlying PBGD mutation should be identified by DNA testing after the diagnosis of AIP is established by biochemical methods.

This not only further confirms the diagnosis, but most importantly enables accurate identification of other gene carriers in a family.

The great majority of heterozygous carriers of PBGD mutations have a good prognosis and remain asymptomatic during their lifetime .

Attacks of acute porphyria are rare in children, thus reducing the urgency of making a diagnosis.

Acute attacks are precipitated by events that either directly induce ALAS1 or increase the demand for haem synthesis. These events include hormonal fluctuations during the menstrual cycle, fasting, smoking, infections, and exposure to porphyrinogenic drugs.

Less than 10% of patients have recurrent acute attacks without clearly identified precipitating factors.

Most drugs that exacerbate porphyria are closely associated with induction of cytochrome P450 enzymes, which increase hepatic haem turnover.

Inflammatory and infectious diseases induce hepatic expression of the acute-phase protein haem oxygenase , which catabolises haem.

We review their medical history and medications, looking for clues that would point to the porphyrias. These include medications that are unsafe for use in the porphyrias, such as the barbiturates and sulfonamides.

Barbiturates or seizure-control medicines affect porphyrias, especially if patients have had new ones added or a dosage changed.

UNSAFE ( INDUCE HEPATIC ALAS1 AND CYPs)

SAFE

Alcohol Barbiturate Carbamazepine rifampin Clonazepam Danazol Diclofenac and other NSAIDS Metoclorpramide Phenytoin Pirimidone Na Valproate Progesterone Rifampin Pyrainamide Sulfanamide AB

Acetaminophen Aspirin Atropine Bromides Cimetidine Epo Gabapentin Gc Insuline narcotic

Treatment should be started promptly and any precipitating factors—especially drugs (including oestrogens and progestagens)—avoided, underlying infection should be treated and hypocaloric diets corrected.

Nutritional factors ALAS1 is upregulated by starvation or other conditions

where glucose level is low . Exacerbation of AIP by reduced intake of calories which may occur during illness, surgery or other stress

They want to maintain a good, regular diet, not one that is low in carbohydrates or low in calories, because those things might precipitate an attack.

They also would want to avoid alcohol and stressful situations that could bring on an attack.

Pain, nausea, and vomiting are generally severe and require narcotic analgesics, chlorpromazine, or another phenothiazine or ondansetron, agents which are safe to use in the acute porphyrias.

Short-acting benzodiazepines in low doses are probably safe for anxiety and insomnia .

Beta-adrenergic blocking agents may be useful to control tachycardia and hypertension.

Careful management of fluid balance, with avoidance of large volumes of hypotonic dextrose, is necessary to limit the risk of severe hyponatraemia, which could provoke convulsions.

Cardiovascular complications such as hypertension and tachycardia are rarely severe, therapy with β blockers is needed in some cases.

Very occasionally, acute attacks are accompanied by a severe adrenergic crisis with dangerous hypertension, encephalopathy and seizures. Intravenous infusion of magnesium sulphate can be effective for control of adrenergic symptoms.

Seizures are treated by carefully correcting hyponatremia, if present.

Almost all anticonvulsant drugs have at least some potential for exacerbating acute porphyrias.

Clonazepam may be less harmful than phenytoin, barbiturates or valproic acid . Bromides, gabapentin, and vigabatrin are safe.

Attacks should be treated with either carbohydrate loading or hemin, both of which repress hepatic delta aminolevulinic acid synthase (ALAS1) and are considered specific therapies.

Glucose and other carbohydrates reduce porphyrin precursor excretion, but the effects are weak compared with those of hemin. Therefore, only attacks with mild pain and without severe manifestations (eg, no paresis or hyponatremia present) should be treated with carbohydrate loading

An adequate intake of calories should be ensured, given orally as carbohydrate-rich food supplements (more than half of energy intake), or infused as normal saline with 5-10% dextrose when the patient has severe vomiting.

Intravenous treatment with 300 to 500 grams of intravenous glucose is recommended.

You are really driving mild hyperglycemia in that patient to help reverse the process.

Intravenous haemin administration, which inhibits upregulated ALAS1 and curtails urinary excretion of 5-aminolaevulinic acid and porphobilinogen, is the specific (or aetiopathogenic) treatment of choice.

Most patients with uncomplicated attacks improve within 5 days. Measurement of urinary porphobilinogen excretion is useful to document the metabolic response to human haemin.

When infused intravenously, these heme preparations become bound mostly to circulating albumin as heme albumin. These are taken up primarily by hepatocytes, where the heme component reconstitutes the regulatory heme pool.

This leads to repression of the synthesis of hepatic ALAS1, followed by dramatic reductions in ALA and PBG in plasma and urine.

However, human haemin will not reverse an established neuropathy, but might prevent neuropathy onset and halt further progression if given sufficiently early.

A stable preparation of human haemin solution stabilised with arginine (Normosang) is widely available, whereas in the USA a form of lyophilised haemin (Panhaematin) is available.

Coagulopathies reported with other haem preparations do not develop with stabilised haemin with arginine.

Administration after 1:1 dilution in 4–20% human serum albumin increases haem solubility and stability and lowers the risk of vein injury.

The standard regimen for the acute attack is 3 to 4 mg/kg of hemin daily for four days. Treatment may be extended if a response is not observed within this time.

Hemin prophylactically administered once or twice weekly can prevent frequent, non-cyclic attacks of porphyria in some patients

Hemin has been administered safely during pregnancy

Subacute or chronic symptoms are unlikely to respond to this agent.

Attacks during pregnancy have been treated without any apparent adverse effects to either mother or child.

Management of repeated attacks that are severe enough to need admission is difficult, and long-term treatment with human haemin is needed. Regular treatment with a once-per-week single dose can help to control the disease.

The most frequently reported event after several courses of haem therapy is the disappearence of the superficial venous system.

Most of these patients will probably need permanent indwelling venous catheters, which have many attendant complications.

A single dose of human haemin contains 22.7 mg of iron. Therefore, iron overload is possible in patients who are given regular doses.

The patient may require a liver biopsy down the road, depending on what their total iron exposure is.

Side effects of hemin: Infusion site phlebitis

other side effect are uncommon and have included fever, aching, malaise, hemolysis, anaphylaxis, and circulatory collapse

Excessive dosing caused reversible acute renal tubular damage in one case

Some patients treated repeatedly with hemin have developed iron overload. Therefore, serum ferritin should be monitored and small-volume phlebotomies considered during remission, with a goal to normalize serum ferritin levels into the range of 100 to 200 ng/mL. Phlebotomy-induced iron deficiency should be avoided.

5-aminolaevulinic acid or other metabolites that are overproduced by the liver are neurotoxic, and this notion is consistent with the substantial benefit of liver transplantation in patients with severe acute intermittent porphyria.

A few patients with severe acute intermittent porphyria have received liver transplants. This intervention returns 5-aminolaevulinic acid and porphobilinogen excretion to normal, abolishes acute attacks, and improves quality of life.

Thus, liver transplantation should be considered for selected patients with the most severe form of acute intermittent porphyria.

Other therapies :

Uncontrolled observations in small numbers of patients suggest that cimetidine is a cost-effective alternative to hemin for treating acute attacks.

Cimetidine inhibits hepatic CYPs, and can prevent experimental forms of porphyria induced by chemicals that are activated by CYPs

However, chemicals activated by CYPs are rarely, if ever, implicated in human AIP.

Therefore, cimetidine cannot be recommended as an alternative to hemin.

If present, iron deficiency, which at least theoretically might further impair heme synthesis, should be corrected.

Frequently recurring attacks confined to the luteal phase of the menstrual cycle can be prevented with a GnRH analogue. If treatment is effective after several months, low-dose estradiol, preferably by the transdermal route, or a bisphosphonate may be added to prevent bone loss and other side effects, or treatment changed to a low-dose oral contraceptive.

In patients with acute porphyrias who have episodes that are worsened during the luteal phase of their menstrual period, a GnRH analog for a period of 2-3 months is often helpful in decreasing the number of episodes that a patient may have.

GnRH analogs have been helpful in reducing attacks in patients with cyclical attacks.

Carriers of the gene defect, symptomatic or not, should be counselled about maintenance of a healthy diet with regular meals, avoidance of alcohol and smoking, and use of the list of potentially safe and unsafe drugs.

Finally, patients with both symptomatic and latent disease have increased risks of hypertension and chronic renal failure.

I would just add to that that for not very well-understood reasons, usually not due to secondary iron overload, these people are at increased risk of developing chronic liver disease, cirrhosis, and hepatocellular carcinoma.

Cutaneous porphyrias Cutaneous porphyrias are associated with :

photosensitivity due to activation of porphyrins in the skin by visible and long wave ultraviolet light (also known as UV-A).

Most cutaneous porphyrias are manifested by chronic blistering skin lesions on sun-exposed areas of the skin, particularly the backs of the hands. If severe, these may become infected and mutilating.