Pellagra

Porphyrias

The porphyrias arise from inherited deficiencies of the enzymes involved in haem biosynthesis. These deficiencies cause toxic effects through the accumulation of haem precursor compounds. Each porphyria is defined by its specific enzyme deficiency. Two kinds of clinical manifestation are seen: neurovisceral abnormalities (usually in the acute porphyrias) and photosensitivity of the skin (usually in the porphyrias whose symptoms appear in the skin).

Haem is an iron-containing pigment produced mostly by erythroblasts and reticulocytes in the bone marrow; it binds to globin to form haemoglobin. Haem is also made in the liver, where it binds to enzymes such as the cytochromes. Haem synthesis requires 8 separate enzymes.

If the porphyrin compounds produced and modified by these enzymes accumulate, their toxic effects appear.

Aetiology and Pathophysiology

The porphyrias result from a deficiency of any one of the last 7 enzymes in the haem biosynthesis chain. A deficiency of the first enzyme in this chain, delta-aminolaevulinic acid (ALA) synthase, causes sideroblastic anaemia. The genetic code for each enzyme is carried by a gene, and changes at countless possible points in this gene are reflected as impaired function of the enzyme it produces. When an enzyme involved in haem biosynthesis is insufficient or deficient, its substrates and precursors accumulate in the bone marrow, liver, skin and other tissues and cause toxicity. The accumulated precursors can also be found in the blood and are excreted in the urine, bile or via the large bowel.

Most porphyrias are autosomal dominant. Homozygous states are usually incompatible with life and lead to fetal death; the exceptions are ALA dehydratase (ALAD) deficiency porphyria and uroporphyrinogen III cosynthase deficiency. These two diseases appear only in homozygous or compound heterozygous states (that is, two separate heterozygous mutations in the same gene in the same patient). In heterozygotes, the penetrance of the disease varies.

Although the most accurate classification of the porphyrias is by the deficient enzyme, distinguishing them by clinical features (phenotype) is generally useful. The porphyrias are therefore divided into 2 classes: acute and cutaneous porphyrias. The acute porphyrias are conditions triggered by medicines and other external causes, with intermittent abdominal, mental and neurological symptoms. The porphyrias affecting the skin cause photosensitivity of the skin with continuous or fluctuating symptoms. Some acute porphyrias also have skin symptoms.

The 2 most frequently diagnosed inherited porphyrias are acute intermittent porphyria (AIP) and porphyria cutanea tarda (PCT). Each occurs with a probability of about 1 in 10,000; however, because the penetrance of heterozygous porphyria is variable, the probability of clinical disease is lower than the genetic probability.

In all porphyrias except ALAD deficiency porphyria and erythropoietic protoporphyria (EPP), a change in urine colour (red or reddish-brown) is seen in the symptomatic phase; the colouring is caused by oxidised porphyrins and/or the porphyrin precursor porphobilinogen (PBG). Sometimes the colouring only shows when the urine is left to stand for about 30 minutes, as the porphyrins oxidise. In the acute porphyrias other than ALAD deficiency porphyria, PBG excretion in the urine (and the colour change) is seen during the latent phase of the disease in one in every 3 heterozygotes (more often in women than in men).

Diagnosis

When signs of porphyria are seen clinically, patients are screened with blood and urine tests for porphyrins or the porphyrin precursors PBG and ALA. Abnormal screening results are supported by further tests.

Patients without symptoms, including those suspected of being carriers of the inherited disorder and patients between two attacks, are assessed in a similar way, but in this situation the test results are less sensitive, and measurements of red blood cells or red cell enzymes are more sensitive. Genetic analysis is highly accurate and should be preferred for families too if the mutation is known. Similar testing can be carried out before birth (by amniocentesis or chorionic villus sampling), but this is rarely indicated.

Acute Porphyrias

In the acute porphyrias there are intermittent episodes of abdominal pain and neurological symptoms, and these attacks are triggered by certain medicines and other factors. In people with variegate porphyria and hereditary coproporphyria, sunlight causes widespread blistering of the skin. The diagnosis is confirmed by measuring high levels of ALA and PBG in the urine during an attack. Treatment is with glucose or, in severe attacks, with intravenous haem. Symptomatic and pain-relief treatment is given as needed.

In order of frequency, the acute porphyrias include acute intermittent porphyria (AIP), variegate porphyria (VP), hereditary coproporphyria (HCP) and the very rare ALAD deficiency porphyria.

In heterozygotes, the acute porphyrias very rarely manifest before puberty, and after puberty the probability is around 20-30%. In homozygotes the disease appears in childhood and its symptoms are severe.

Precipitating Factors

Many factors that trigger the disease raise the rate of haem biosynthesis beyond the working capacity of the impaired or reduced enzyme. The porphyrin precursors porphobilinogen (PBG) and delta-aminolaevulinic acid (ALA) (or ALA alone in ALA dehydratase [ALAD] deficiency porphyria) accumulate.

Hormonal factors are important. Women are more prone to attacks than men, especially at times of hormonal change (e.g. before menstruation, while taking contraceptive hormones, in the first weeks of pregnancy or immediately after giving birth). Nevertheless, pregnancy is not contraindicated.

Other factors include medicines (barbiturates, other antiepileptics, sulphonamide antibiotics and reproductive hormones (progesterone and similar steroids)), particularly those that induce ALA synthase and cytochrome P-450 enzymes in the liver. Attacks generally appear 24 hours after the medicine is taken. Low-calorie or low-carbohydrate diets and alcohol intake also trigger attacks. Stress arising from infection, other illnesses, surgery or mental problems is considered a separate factor. Attacks usually occur through a combination of several factors or for unknown reasons.

Sunlight causes skin symptoms in VP and HCP.

Symptoms and Signs

Symptoms and signs involve the nervous system, the abdomen, or both (neurovisceral symptoms). Symptoms develop over hours or days and can last up to several weeks. Some gene carriers have only a few attacks in their lifetime, while others have recurrent symptoms. In women, attacks often coincide with phases of the menstrual cycle.

Acute porphyria attack: Symptoms typical of the period before an acute attack are constipation, tiredness, irritability and insomnia. The most common attack symptoms in patients are abdominal pain and vomiting. The abdominal pain can be very severe and is out of proportion to abdominal tenderness. The abdominal symptoms may result from involvement of the intestinal nerves or from ischaemia caused by local vasoconstriction. Because there is no inflammation, the abdomen is not tender and there are no peritoneal signs. Body temperature and white blood cell count are normal or slightly raised. Intestinal paralysis (ileus) can cause distension and bloating of the bowel. The urine is red or reddish-brown, and urinary PBG levels are high throughout the attack.

All components of the peripheral and central nervous system can be affected. Motor neuropathy is common and severe, in the form of prolonged attacks. Muscle weakness usually begins in the hands and feet but can affect any motor neuron or cranial nerve, causing quadriplegia. When the medulla oblongata is affected, respiratory failure occurs.

Involvement of the central nervous system causes seizures and mental and behavioural changes (apathy, depression, agitation, overt psychosis, hallucinations), which may result from reduced sodium or magnesium levels that also contribute to heart rhythm disturbances.

Excessive release of catecholamines causes restlessness and tachycardia, and catecholamine-induced arrhythmia can, though rarely, result in sudden death. Labile hypertension, characterised by temporary rises in blood pressure, can turn into persistent hypertension if untreated, through the changes it causes in the blood vessels. Kidney failure in the acute porphyrias is multifactorial; acute hypertension (which may become persistent) aggravates kidney failure.

Subacute/subchronic symptoms: Some patients have longer-lasting but less severe symptoms (constipation leading to obstruction, tiredness, headache, back and thigh pain, paraesthesia, rapid heartbeat, respiratory insufficiency, insomnia, mental disturbances, seizures).

Skin symptoms in VP and HCP: Even in the absence of neurovisceral symptoms, skin fragility and widespread blistering occur in sun-exposed areas, but patients usually do not notice the connection with sunlight. The skin symptoms are identical to those of PCT.

Late symptoms: Involvement of the motor nerves can cause permanent weakness between attacks. In patients with AIP, and possibly VP and HCP, especially those who have previously had porphyria attacks, liver cancer, hypertension and kidney failure are also more common after middle age.

Diagnosis

Acute attack: An acute porphyria attack cannot be distinguished from acute abdominal crises due to other causes (sometimes unnecessary surgery may be performed). The same applies to primary neurological or psychiatric disorders. The possibility of porphyria should be considered in people already known to carry a porphyria gene or with a family history of porphyria, but other causes should also be considered in carriers.

The most important finding is red urine that was not present before the attack and appears with it. A urine sample should be taken and assessed, particularly in a patient with severe constipation, vomiting, rapid heartbeat, muscle weakness, bulbar or mental symptoms and abdominal pain.

When porphyria is suspected, PBG should be measured by rapid qualitative or semi-quantitative methods. If the result is positive, the exact levels of ALA and PBG should be measured in the same urine sample. Unless the person being assessed is a gene carrier who excretes high levels of porphyrin precursors in the urine even in the latent phase of the disease, values >5 times higher than normal indicate an acute porphyria attack.

If urinary ALA and PBG levels are normal, other diagnoses should be considered. Raised ALA with normal or slightly raised PBG may indicate lead poisoning or ALAD deficiency porphyria. A random urine sample is adequate; a 24-hour urine collection is of no benefit. ALA and PBG measurements should be corrected for the creatinine content of the sample. Electrolytes and Mg should be measured. Sodium deficiency may occur due to low-salt fluid therapy for excessive vomiting or diarrhoea, or due to the syndrome of inappropriate antidiuretic hormone secretion.

Determining the type of porphyria: Identifying the specific type of porphyria does not affect treatment, but it is useful for finding gene carriers among relatives. Each type has its own characteristic pattern of porphyrin and porphyrin-precursor accumulation and excretion in plasma, urine and faeces. If high urinary ALA and PBG are found, faecal porphyrins should be measured. If these are normal or slightly raised, this indicates AIP; if markedly raised, it indicates HCP or VP, and they are not seen outside an attack. In the acute porphyrias affecting the skin, plasma porphyrins showing their own characteristic fluorescence are often seen. If the red blood cell PBG deaminase enzyme has fallen to about 50% of normal, AIP is considered. If protoporphyrinogen oxidase is reduced, VP is considered, and if coproporphyrinogen oxidase is reduced, HCP is considered.

Family studies: The child of a carrier of the defective gene has a 50% risk of inheriting the gene. Because early diagnosis and family counselling reduce the risk of morbidity in children, children in affected families should be screened as early as possible. If the disease genotype has been identified in the first family member shown to carry the porphyria gene, genetic screening can be carried out; if not, the relevant enzymes are measured in red and white blood cells. Genetic analysis for diagnosis in the womb can be carried out by amniocentesis or chorionic villus sampling, but it is generally not needed because the outlook for gene carriers is favourable.