Hepatoerythropoietic Porphyria: Understanding A Rare Genetic Disorder

Introduction

Hepatoerythropoietic porphyria (HEP), a hepatic (liver-related) and cutaneous (skin-affecting) form of porphyria, is an exceptionally rare genetic disorder. HEP falls within the group of diseases known as porphyrias,¹ and it is characterised by blistering skin lesions, hypertrichosis (excessive hair growth), and scarring over the affected skin areas.²

Due to its scarcity and the severe symptoms it manifests, it is vital to shed a light on this condition; understanding HEP is significant for medical professionals, and even more significant for patients and their families. Therefore, in this comprehensive article, we delve into the genetic causes, symptoms, diagnosis, treatment, and the impact of HEP on patients' lives. 

Overview of porphyrias

Porphyrias refers to a group of rare disorders that result from a build-up of naturally-occuring chemicals called porphyrins in the body. Porphyrins are essential to make heme, a vital component of haemoglobin. Haemoglobin itself is a protein within red blood cells, that is responsible for transporting oxygen to the body’s organs and tissues.

There are eight enzymes (biological catalysts that speed up the rates of chemical reactions) that are required to turn porphyrins into heme, and a deficiency in one of these results in the subsequent build-up of porphyrins. When porphyrins are in high concentrations, they can cause major problems, mainly in the nervous system and the skin. The two main types of porphyrias are acute porphyrias, which start rapidly and mainly affect the nervous system, and cutaneous porphyrias, which mainly affect the skin. However, there are also a few types where both the nervous system and the skin are affected. The symptoms of the condition depend on the type of porphyria that the individual has. Regardless, porphyria cannot be cured, and it can only be managed by medicine and lifestyle changes.³

Genetic causes of hepatoerythropoietic porphyria

HEP is an autosomal recessive condition. This means that HEP is inherited only if both parents are known to be heterozygous (have two different versions of a gene) or homozygous (the same version of a gene) for the mutated UROD gene. If the parents are heterozygous, there will be a 25% chance of inheriting the condition, 50% of being a carrier (it doesn’t present any symptoms), and 25% of not having the mutated gene. For these reasons, if relatives of one or both of the parents have a history of HEP, genetic testing might be recommended.⁴

The UROD gene is responsible for the encoding of an enzyme known as uroporphyrinogen decarboxylase (UROD), which is the fifth enzyme in the heme biosynthetic pathway. In HEP, the activity of the UROD enzyme is typically less than 10% of its normal levels. As mentioned previously, this deficiency in activity results in the abnormal accumulation of certain porphyrins and related chemicals, especially within the bone marrow, red blood cells, liver and skin, leading to the development of the symptoms described in the paragraphs below.⁵

Symptoms and clinical presentation

HEP usually presents early in life, as in most cases, the onset is within the first two years of the life of an infant. However, due to the nature of the symptoms and the severity of HEP, which varies from person to person, some individuals with mild symptoms may remain undiagnosed until adulthood. This may also occur due to the small number of identified cases, as despite the specific associated characteristic symptoms, there are still several other factors that have not yet been associated with the disorder.

Frequently, the first sign of HEP is severe cutaneous photosensitivity. Commonly, infants affected by this symptom may have extremely fragile skin that can peel or blister with minimal impact and exposure to the sun. Moreover, the redding of the skin (erythema) is also a symptom that is often observed. This photosensitivity can be severe, and in some instances, it may cause scarring, erosion, and disfigurement of the skin. In addition, as a result of the increased sensitivity of the skin, bacterial infections of skin lesions can occur.

Another common symptom is abnormal, excessive hair growth (hypertrichosis), which may also occur on sun-exposed skin. Affected skin may also suffer from colour alteration, which can either be darkening (hyperpigmentation) or lighter (hypopigmentation). Furthermore, small bumps with a distinct white head (milia) may also develop. Some affected individuals may also have reddish-brown coloured teeth.

Affected individuals may also have anaemia, a condition that is characterised by low levels of circulating blood. Anaemia may develop due to the premature destruction of red blood cells (haemolysis). Anaemia may vary in severity from mild to severe. If the affected individual has severe anaemia, they may also feel fatigued and have pale skin, irregular heartbeat, chest pain, dizziness, and abnormally cold hands and feet. Additionally, some individuals may have an enlarged liver and/or spleen (hepatosplenomegaly).⁶

Diagnosis

Early diagnosis of HEP is crucial for the effective management and prevention of complications. However, the rarity of the condition often leads to misdiagnosis or delayed diagnosis, making the requirement for awareness among healthcare professionals critical.

HEP is diagnosed based on the identification of characteristic symptoms, a detailed patient history, a thorough clinical evaluation, and a variety of specialised tests. Mainly, HEP is suspected and considered in infants and children with chronic, blistering photosensitivity.

Genetic testing is one of the primary diagnostic tools for HEP. It involves analysing the UROS gene to identify the mutations that cause the dysfunctional enzyme, where the requirement for determining if HEP is indeed present is to verify that the two mutated copies of the UROS gene are there. 

In addition to genetic testing, some specialised tests that suspected individuals might undertake are urine and blood tests. These are used to detect elevated levels of porphyrins and their precursors.⁷

Treatment and management

Currently, no clinical practice guidelines for HEP have been published. However, the treatment for HEP is patient-centred and is therefore directed towards the specific symptoms that each individual presents. Due to the wide variety of symptoms that individuals may present with, treatment may require the coordinated efforts of a multidisciplinary team. Such teams involve different specialists who come together to devise the best course of treatment for each individual to address their needs.

Since HEP is a genetic disorder, there is no cure as of yet, as there are no effective treatment regimens that restore UROD enzyme activity levels to normal.

Nevertheless, the present treatment/management recommendation is similar to the one suggested for those with familial porphyria cutanea tarda (F-PCT). This includes:

• Prompt treatment of any infection superimposed on skin lesions.
• Low-dose chloroquine and oral charcoal (to bind stool porphyrins) have been used in specific circumstances with variable success.
• Strict avoidance of sunlight, including the long-wave ultraviolet light sunlight that passes through window glass, is necessary because of the high risk for severe skin damage and possible mutilation.
• Identification and avoidance of susceptibility factors (where applicable).
• Avoidance of drugs and agents that induce the hepatic cytochrome P450s.
• Routine vaccination against hepatitis A and B.

Moreover, monitoring the condition may also be suggested to regulate urinary porphyrin levels and other symptoms.⁸

However, from an optimistic outlook, ongoing research provides a hopeful prospect for the individuals affected by the condition and their carers. You can find further information about the clinical trials regarding HEP on the website links for the EU Clinical Trials Register and for US Clinical Trials.

Prognosis

Due to HEP having such a low prevalence rate (less than 1/1,000,000 people), fewer than 40 cases have been described. Current information states that long-term prognosis is favourable given that the affected individuals are diagnosed and receive the required and adequate treatment to manage their symptoms.⁹

Conclusion

The rarity and complex nature of HEP underscore the importance of delving into the intricacies of this disorder to better understand its causes, effects, and potential avenues for treatment. This comprehensive exploration has illuminated the key facets of HEP; from its genetic underpinnings, to its clinical manifestations and management strategies.

One of the fundamental takeaways from this article is the significance of early diagnosis. Given the rarity of HEP incidence,  misdiagnosis or delayed diagnosis is not an uncommon occurrence. However, with an increased awareness among healthcare professionals and the growing availability of genetic testing, there is hope for a quicker and more accurate identification of affected individuals. Early diagnosis is pivotal in preventing the progression of symptoms and improving the overall quality of life for those living with HEP.

The genetic aspect of HEP cannot be overstated. Understanding the autosomal recessive inheritance pattern and the specific mutations in the UROS gene provides critical insights into the origins of this disorder, offering promise for future treatments and perhaps even a cure.

The symptoms of HEP, including photosensitivity, skin fragility, and anaemia, have a profound impact on the patient's daily lives. Managing these symptoms requires a multifaceted approach, ranging from protective measures to medical interventions. Despite the challenges, individuals with HEP can lead fulfilling lives by implementing necessary lifestyle modifications and accessing the support and resources available within the Porphyria community.

One theme that has been repeatedly mentioned throughout this article is the importance of collaboration. The rarity of HEP necessitates a collective effort from healthcare professionals, researchers, patients, and advocacy groups. By pooling knowledge, sharing experiences, and promoting research, we can advance our understanding of HEP and work towards better diagnostic methods and treatments.

To summarise, HEP remains a complex and challenging disorder. However, with ongoing research, increased awareness, and a supportive community, the scientific world is continually making strides towards improved diagnoses, treatment, and, ultimately, a brighter future for individuals affected by HEP.