What are the other Names for this Condition? (Also known as/Synonyms)

• Mixed Hepatic Porphyria
• Mixed Porphyria
• South African Genetic Porphyria

What is Variegate Porphyria? (Definition/Background Information)

• Porphyrias are disorders resulting from excess porphyrin buildup in the liver and bone marrow. Manufacturing hemoglobin and related proteins (heme synthesis) involves a class of molecules called porphyrins. Porphyrias are either inherited or acquired, and are described as acute, chronic, and cutaneous
• Variegate Porphyria (VP) is a rare congenital condition affecting heme metabolism, but normally having an onset during early adulthood. It is similar to acute intermittent porphyria and is triggered by external/internal factors; but additionally, in VP, skin involvement is noted
• Variegate Porphyria is an acute and cutaneous form of porphyria that is typically inherited in an autosomal dominant manner, due to mutations in the PPOX gene, which causes a defect in heme production in the bone marrow and liver. VP is termed as a hepatic porphyria, meaning that the porphyrin compounds accumulate in the liver. This form of porphyria is more common among the South African population
• During acute attacks (presentation of severe symptoms, which are not very long-lasting), the disorder is characterized by severe abdominal pain, constipation or diarrhea, and neurological symptoms that include muscle pain and weakness. Additionally, light-sensitivity of the skin (on exposure to sunlight), results in skin abnormalities including blistering and ulceration
• A healthcare provider typically diagnoses this genetic disorder by testing porphyrin levels in body fluid samples, along-with symptom assessment. Establishing the presence of increased levels of porphyrin compounds in urine, blood, or feces can help confirm the diagnosis
• The treatments for Variegate Porphyria involves removing or treating the triggers causing VP and symptomatic treatment. It also involves administering intravenous heme and the use of suitable sun protection creams. In many, the symptoms of an acute attack subside on their own
• The prognosis of Variegate Porphyria is determined by the severity of symptoms and whether complications have developed. In many individuals, the prognosis is good with adequate treatment. However, individuals presenting symptoms early in childhood, may have poorer outcomes

Who gets Variegate Porphyria? (Age and Sex Distribution)

• Variegate Porphyria (VP) is an uncommon genetic condition. But, it is reported to affect individuals of certain populations more than others
  • Among the Caucasians of South Africa, VP is reported as affecting 1 in 300 individuals
  • In Finland, VP is reported in 1 in 75,000 individuals 
  • The condition is also seen at a higher incidence in other European countries, such as Sweden and Switzerland, and Argentina and Australia
• Since, it is a congenital disorder, the condition is present at birth but without signs and symptoms. However, generally the onset of symptoms is noted in young adults and occasionally by puberty. Sometimes, symptoms are first noted among older adults
• Both male and female genders are affected

What are the Risk Factors for Variegate Porphyria? (Predisposing Factors)

• A family history of Variegate Porphyria (VP) increases the risk of a newborn being diagnosed with the condition, since VP is an inherited disorder
• A higher incidence of VP is observed in the Caucasian population of South Africa and individuals of Finnish descent

It is important to note that having a risk factor does not mean that one will get the condition. A risk factor increases one’s chances of getting a condition compared to an individual without the risk factors. Some risk factors are more important than others.

Also, not having a risk factor does not mean that an individual will not get the condition. It is always important to discuss the effect of risk factors with your healthcare provider.

What are the Causes of Variegate Porphyria? (Etiology)

Variegate Porphyria (VP) is caused by mutations in the PPOX gene on chromosome 1, which is involved in the production of “heme”.

• Heme is a critical component of iron-containing proteins called hemoproteins. Hemoglobin is one such protein, which is the oxygen carrier in blood. Blood, bone marrow, and liver have the most heme protein in them
• Mutations in the PPOX gene are inherited in an autosomal dominant manner. Mutations in this gene affects porphyrin metabolism. A compromised porphyrin metabolism causes a buildup of porphyrins in the body
• Variegate Porphyria is described as a type of porphyria affecting the liver (hepatic porphyria), because porphyrin compounds collect in the liver in excessive amounts
• This mutation affects the function of the specific enzyme protoporphyrinogen oxidase (PPO), in the red blood cells and liver. The activity of PPO enzyme is affected by a factor of 50% or more, which disrupts heme synthesis
• In the presence of other internal or external triggers, it results in an acute attack, due to the abnormal accumulation of porphyrin compounds in the body

The external factors or triggers may include:

• Environmental stimuli
• Eating an unusual diet; starvation
• Illegal drug abuse
• Alcoholism
• Use of certain medications

The internal factors may include:

• Emotional or psychological stress
• Menstruation in women: Some research scientists believe that periodic menstrual cycles may not trigger acute attacks of VP
• Any illness or infection
• Other hormonal factors

Note: Studies have also not established that certain chronic mental disorders can cause the symptoms of Variegate Porphyria.

Autosomal dominant: Autosomal dominant conditions are traits or disorders that are present when only one copy of the mutation is inherited on a non-sex chromosome. In these types of conditions, the individual has one normal copy and one mutant copy of the gene. The abnormal gene dominates, masking the effects of the correctly function gene. If an individual has an autosomal dominant condition, the chance of passing the abnormal gene on to their offspring is 50%. Children, who do not inherit the abnormal gene, will not develop the condition or pass it on to their offspring.

What are the Signs and Symptoms of Variegate Porphyria?

The various signs and symptoms of Variegate Porphyria (VP) stem from the buildup of porphyrin compounds in the body and may include the following:

• Stomach pain and cramping abdominal pain
• Diarrhea or constipation
• Retention of urine
• Since, liver involvement is present in VP, yellowing of skin and eyes may be observed
• The skin is light-sensitive, and thus, exhibits the following symptoms (on exposure to direct sunlight):
  • Skin gets inflamed with burning sensation
  • Blister formation can take place; skin rashes are seen
  • Over time, the skin becomes fragile and weak
  • Peeling or eroding away of skin
  • Chronic skin conditions may include thickened skin, change of color (abnormal pigmentation), and excessive hair growth
• Neurological signs and symptoms may include:
  • Peripheral neuropathy
  • Muscular pain and weak muscles; lethargy
  • If the respiratory muscles are affected, it may cause breathing difficulties
  • Seizures in some cases
• When the nervous system of the internal organs is affected, it gives rise to neurovisceral crises
• Psychiatric signs and symptoms may include:
  • Change in sensation
  • Feeling confused
  • Hallucinating
• Abnormal color of urine (reddish) on exposure to sunlight; which tends to resolve following treatment, or when the symptoms go away

The signs and symptoms of Variegate Porphyria are not as long-lasting as those of acute intermittent porphyria, even though both present with severe symptoms.

How is Variegate Porphyria Diagnosed?

The diagnosis of Variegate Porphyria is made by the following tools:

• A complete physical examination and an assessment of symptoms
• An evaluation of the affected individual’s full medical history
• Measurement of the porphyrin levels in blood, urine, or feces
  • Urine screening test (24 hours): Reddish urine is observed during attacks, due to presence of porphyrins; although, increased PBG and ALA in urine is mostly/always observed. If porphyrin levels in urine are very high, it may imply that the attacks are more severe
  • Assessment of blood levels of porphyrin compounds
  • Assessment of stool levels of porphyrin compounds
• Measurement of protoporphyrinogen oxidase (PPO) enzyme activity: It is difficult to measure PPO enzyme in blood
• Molecular genetic testing before or after birth, to confirm PPOX gene mutations

Note: When no attacks are seen, or in the period between attacks, the urine levels may be normal. Carriers, who do not show any symptoms, regularly have normal urine/feces levels of porphyrin compounds.

Many clinical conditions may have similar signs and symptoms. Your healthcare provider may perform additional tests to rule out other clinical conditions to arrive at a definitive diagnosis.

What are the possible Complications of Variegate Porphyria?

The potential complications of Variegate Porphyria may include:

• Severe pain and emotional stress during periods of acute attacks
• Recurrent skin infections (via bacteria or virus)
• Cosmetic issues due to skin of the face, neck, arms being chronically affected
• Anemia and related conditions, due to low levels of oxygen transport
• Increased heart rate and increased blood pressure may be the outcome of autonomic nervous system being affected
• If the neuroendocrine region of brain is affected, it can lead to hyponatremia and hypomagnesemia (low sodium and magnesium levels in blood respectively), resulting in additional complications
• The affected individuals are vulnerable to hepatocellular carcinoma (HCC); hence, they should be periodically monitored

How is Variegate Porphyria Treated?

The treatment of Variegate Porphyria may include:

• When the first signs of disease are recognized, the individual is given oral/intravenous glucose (called glucose loading) and carbohydrate-rich diet
• Medications to control severity of the acute attacks
• Large dose and strong painkillers (narcotic analgesics or opiates) may be given for severe pain
• Antipsychotic medication (chlorpromazine) to treat some of the neurological symptoms, antidepressants for depression
• Beta-blockers, such as propranolol, for cardiovascular conditions (such as hypertension and tachycardia)
• Anti-seizure medications (such as gabapentin) for seizure
• Blood disorder medications (intravenous heme or hematin) may be used to treat accumulation of the compounds
• Skin-related recommendations for affected individuals include the following:
  • Avoiding direct exposure to sunlight
  • Visible light, not ultraviolet, triggers the skin sensitivity in porphyrias. Zinc oxide/titanium oxide-based sunscreens can help when used in quantities that leave a white film
• Blood transfusions, based on the severity of anemia
• A splenectomy (removal of the spleen) to alleviate bleeding and worsening anemia (due to spleen enlargement)
• Bone marrow transplant for severe cases

In many individuals, the symptoms of an acute attack subside on their own. Sometimes, it may be severe as to requiring treatment in a hospital setting. The treatment also involves removing or treating any internal or external triggers.

How can Variegate Porphyria be Prevented?

Currently, there are no specific methods or guidelines to prevent Variegate Porphyria (VP), since it is a genetic condition.

• Genetic testing of the expecting parents (and related family members) and prenatal diagnosis (molecular testing of the fetus during pregnancy) may help in understanding the risks better during pregnancy
• If there is a family history of the condition, then genetic counseling will help assess risks, before planning for a child
• Active research is currently being performed to explore the possibilities for treatment and prevention of inherited and acquired genetic disorders such as Variegate Porphyria

Regular medical screening at periodic intervals with tests and physical examinations are highly recommended.

Once the triggers or precipitating factors for VP are identified, certain steps may be taken to avoid them to the extent possible, such as:

• Having a healthy lifestyle and a regular diet
• Stress avoidance, when possible
• Avoid the use of illegal drugs; avoiding alcohol
• Discontinuing medicines that trigger VP, instead using alternatives
• Undertaking prompt treatment for any illness or infection

Individuals with Variegate Porphyrias are encouraged to wear an emergency (medical) identification tag or suitable bracelet to inform providers/others about their condition, which is particularly helpful in case of an acute attack.

What is the Prognosis of Variegate Porphyria? (Outcomes/Resolutions)

• The prognosis of Variegate Porphyria (VP) varies with the severity of the condition. But, it is generally good for mild cases and the symptoms go away with adequate treatment. Also, carriers showing signs and symptoms of VP have good prognosis
• If neurological symptoms are severe involving the muscle and sensory faculties, then recovery may be prolonged, and it may take many months
• Individuals with an early-onset of signs and symptoms (such as during infancy) may have poorer outcomes than those with late onset, due to increased severity of the condition

Additional and Relevant Useful Information for Variegate Porphyria:

Hereditary coproporphyria (HCP) is the only other form of porphyria that is classified as both an acute and cutaneous form of porphyria, apart from Variegate Porphyria.