Porphyrias

Porphyrias are a group of metabolic disorders caused by a disturbance in the synthesis of heme. In most cases, porphyria is caused by a hereditary enzyme defect. The disease patterns differ depending on the affected enzyme, and the variants of porphyria can be clinically differentiated between acute and nonacute forms. Patients with porphyria present with photosensitive skin Skin The skin, also referred to as the integumentary system, is the largest organ of the body. The skin is primarily composed of the epidermis (outer layer) and dermis (deep layer). The epidermis is primarily composed of keratinocytes that undergo rapid turnover, while the dermis contains dense layers of connective tissue. Structure and Function of the Skin eruptions and sometimes systemic symptoms such as abdominal pain Pain Pain has accompanied humans since they first existed, first lamented as the curse of existence and later understood as an adaptive mechanism that ensures survival. Pain is the most common symptomatic complaint and the main reason why people seek medical care. Physiology of Pain and neuropathy. Porphyrias are managed by avoiding triggers, such as sun exposure and consumption of alcohol. When flares occur, therapy is targeted toward symptomatic relief.

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Definition and Epidemiology

Definition

Porphyrias are rare metabolic disorders caused by impairments in heme synthesis.

  • Characterized by a buildup of substances called porphyrins
  • Types of porphyria are differentiated by the type of porphyrin that accumulates in the blood, urine, or stool.
  • May affect the skin Skin The skin, also referred to as the integumentary system, is the largest organ of the body. The skin is primarily composed of the epidermis (outer layer) and dermis (deep layer). The epidermis is primarily composed of keratinocytes that undergo rapid turnover, while the dermis contains dense layers of connective tissue. Structure and Function of the Skin, liver Liver The liver is the largest gland in the human body. The liver is found in the superior right quadrant of the abdomen and weighs approximately 1.5 kilograms. Its main functions are detoxification, metabolism, nutrient storage (e.g., iron and vitamins), synthesis of coagulation factors, formation of bile, filtration, and storage of blood. Liver, and nervous system Nervous system The nervous system is a small and complex system that consists of an intricate network of neural cells (or neurons) and even more glial cells (for support and insulation). It is divided according to its anatomical components as well as its functional characteristics. The brain and spinal cord are referred to as the central nervous system, and the branches of nerves from these structures are referred to as the peripheral nervous system. General Structure of the Nervous System

Epidemiology

  • Incidence: approximately 5 cases per 100,000 population
  • Most common type is porphyria cutanea tarda (PCT).
  • 2nd most common type is acute intermittent porphyria.

Pathophysiology

Porphyrias are due to enzymatic defects in heme biosynthesis:

  • Heme is produced in the liver Liver The liver is the largest gland in the human body. The liver is found in the superior right quadrant of the abdomen and weighs approximately 1.5 kilograms. Its main functions are detoxification, metabolism, nutrient storage (e.g., iron and vitamins), synthesis of coagulation factors, formation of bile, filtration, and storage of blood. Liver and bone marrow Bone marrow Bone marrow, the primary site of hematopoiesis, is found in the cavities of cancellous bones and the medullary canals of long bones. There are 2 types: red marrow (hematopoietic with abundant blood cells) and yellow marrow (predominantly filled with adipocytes). Composition of Bone Marrow.
  • Involves 8 enzymatic steps, starting with glycine
  • Enzyme absence or dysfunction leads to buildup of heme precursors.
  • Excess precursors accumulate in tissues, leading to clinical symptoms.
Table: Porphyrias and their associated defective enzyme
Form of porphyria Defective enzyme
Porphyria cutanea tarda Uroporphyrinogen III decarboxylase
Acute intermittent porphyria Porphobilinogen deaminase
X-linked protoporphyria δ-Aminolevulinic acid synthase 2
Congenital erythropoietic porphyria Uroporphyrinogen III synthase
Hereditary coproporphyria Coproporphyrinogen oxidase
Variegate porphyria Protoporphyrinogen oxidase
Erythropoietic protoporphyria Ferrochelatase

Most commonly, porphyrias are due to an inherited enzyme defect within the heme biosynthesis pathway. They may rarely be acquired later in life:

  • Alcohol abuse
  • Infections (e.g., hepatitis C Hepatitis C Hepatitis C is an infection of the liver caused by the hepatitis C virus (HCV). The infection can be transmitted through infectious blood or body fluids and may be transmitted during childbirth or through IV drug use or sexual intercourse. Hepatitis C virus can cause both acute and chronic hepatitis, ranging from a mild to a serious, lifelong illness including liver cirrhosis and hepatocellular carcinoma (HCC). Hepatitis C Virus and HIV/AIDS)
  • Increased estrogen levels

Clinical Presentation

Clinical presentation depends on the pattern of organ involvement.

  • Chronic porphyria → increased skin Skin The skin, also referred to as the integumentary system, is the largest organ of the body. The skin is primarily composed of the epidermis (outer layer) and dermis (deep layer). The epidermis is primarily composed of keratinocytes that undergo rapid turnover, while the dermis contains dense layers of connective tissue. Structure and Function of the Skin manifestations (e.g., blisters and erosions)
  • Acute porphyria → systemic findings (e.g., abdominal pain Pain Pain has accompanied humans since they first existed, first lamented as the curse of existence and later understood as an adaptive mechanism that ensures survival. Pain is the most common symptomatic complaint and the main reason why people seek medical care. Physiology of Pain, liver Liver The liver is the largest gland in the human body. The liver is found in the superior right quadrant of the abdomen and weighs approximately 1.5 kilograms. Its main functions are detoxification, metabolism, nutrient storage (e.g., iron and vitamins), synthesis of coagulation factors, formation of bile, filtration, and storage of blood. Liver enzyme elevation)
  • Most common forms:
    • Porphyria cutanea tarda
    • Acute intermittent porphyria 
    • Erythropoietic protoporphyria:
      • Congenital erythropoietic porphyria (autosomal recessive)
      • Erythropoietic protoporphyria ( autosomal dominant Autosomal dominant Autosomal inheritance, both dominant and recessive, refers to the transmission of genes from the 22 autosomal chromosomes. Autosomal dominant diseases are expressed when only 1 copy of the dominant allele is inherited. Autosomal Recessive and Autosomal Dominant Inheritance)

Porphyria cutanea tarda

  • Most common porphyria
  • Caused by defect in uroporphyrinogen III decarboxylase
  • Can be inherited in an autosomal dominant Autosomal dominant Autosomal inheritance, both dominant and recessive, refers to the transmission of genes from the 22 autosomal chromosomes. Autosomal dominant diseases are expressed when only 1 copy of the dominant allele is inherited. Autosomal Recessive and Autosomal Dominant Inheritance manner or acquired later in life
  • Acquired PCT can be triggered by:
    • Alcohol abuse
    • Exogenous estrogens
    • Infection (often hepatitis C Hepatitis C Hepatitis C is an infection of the liver caused by the hepatitis C virus (HCV). The infection can be transmitted through infectious blood or body fluids and may be transmitted during childbirth or through IV drug use or sexual intercourse. Hepatitis C virus can cause both acute and chronic hepatitis, ranging from a mild to a serious, lifelong illness including liver cirrhosis and hepatocellular carcinoma (HCC). Hepatitis C Virus)
  • Leads to buildup of uroporphyrinogen III
  • Symptoms include:
    • Photosensitivity of skin Skin The skin, also referred to as the integumentary system, is the largest organ of the body. The skin is primarily composed of the epidermis (outer layer) and dermis (deep layer). The epidermis is primarily composed of keratinocytes that undergo rapid turnover, while the dermis contains dense layers of connective tissue. Structure and Function of the Skin
    • Blistering skin Skin The skin, also referred to as the integumentary system, is the largest organ of the body. The skin is primarily composed of the epidermis (outer layer) and dermis (deep layer). The epidermis is primarily composed of keratinocytes that undergo rapid turnover, while the dermis contains dense layers of connective tissue. Structure and Function of the Skin lesions
    • Scars on face and back of hands
    • Hypertrichosis
    • Hyperpigmentation
  • Porphyrin deposits cause progressive liver Liver The liver is the largest gland in the human body. The liver is found in the superior right quadrant of the abdomen and weighs approximately 1.5 kilograms. Its main functions are detoxification, metabolism, nutrient storage (e.g., iron and vitamins), synthesis of coagulation factors, formation of bile, filtration, and storage of blood. Liver damage:
    • Elevated liver Liver The liver is the largest gland in the human body. The liver is found in the superior right quadrant of the abdomen and weighs approximately 1.5 kilograms. Its main functions are detoxification, metabolism, nutrient storage (e.g., iron and vitamins), synthesis of coagulation factors, formation of bile, filtration, and storage of blood. Liver function enzymes Enzymes Enzymes are complex protein biocatalysts that accelerate chemical reactions without being consumed by them. Due to the body's constant metabolic needs, the absence of enzymes would make life unsustainable, as reactions would occur too slowly without these molecules. Basics of Enzymes
    • Liver nodules can be detected on ultrasound.
  • Patients will have dark-colored urine due to elevated uroporphyrins.
Erosions, crust, and blisters are evident on the hands of this patient with pct

Erosions, crust, and blisters are evident on the hands of this patient with porphyria cutanea tarda.

Image: “Erosions, crust, and blisters are evident on the hands of this patient with porphyria cutanea tarda” by Department of Internal Medicine, Minia University, Minia, Egypt. License: CC BY 2.5

Acute intermittent porphyria

  • 2nd most common porphyria
  • Peak incidence: 3rd decade of life
  • Porphobilinogen deaminase is the affected enzyme. Increase in preceding intermediates in metabolic pathway:
    • Porphobilinogen (PBG)
    • δ-Aminolevulinic acid (ALA)
  • Symptoms include:
    • Colicky abdominal pain Pain Pain has accompanied humans since they first existed, first lamented as the curse of existence and later understood as an adaptive mechanism that ensures survival. Pain is the most common symptomatic complaint and the main reason why people seek medical care. Physiology of Pain
    • Neurologic abnormalities
    • Disorientation

Congenital erythropoietic porphyria

  • Caused by defect in uroporphyrinogen III synthase
  • Symptoms include:
    • Skin photosensitivity: blister formation
    • Erythrodontia (red teeth Teeth Normally, an adult has 32 teeth: 16 maxillary and 16 mandibular. These teeth are divided into 4 quadrants with 8 teeth each. Each quadrant consists of 2 incisors (dentes incisivi), 1 canine (dens caninus), 2 premolars (dentes premolares), and 3 molars (dentes molares). Teeth are composed of enamel, dentin, and dental cement. Teeth)
    • Colicky abdominal pain Pain Pain has accompanied humans since they first existed, first lamented as the curse of existence and later understood as an adaptive mechanism that ensures survival. Pain is the most common symptomatic complaint and the main reason why people seek medical care. Physiology of Pain
Erythrodontia in congenital erythropoietic porphyria

Photograph showing the presence of lesions and scars on both hands of a patient with congenital erythropoietic porphyria

Image: “Erythrodontia in congenital erythropoietic porphyria” by Department of Oral Pathology and Microbiology, Kamineni Institute of Dental Sciences, Narketpalli, Andhra Pradesh, India. License: CC BY 2.0

Diagnosis

The diagnosis of porphyrias is typically made using specialized blood tests.

  • If suspected, can screen with urine and blood tests:
    • Urine would have elevated PBG levels.
      • PBG is 1 of the 1st substances in the porphyrin synthesis pathway.
      • Other urinary porphyrins may also be elevated.
    • Serum porphyrins will be elevated.
  • Discolored urine when left standing (yellow to dark red)
  • PBG also detected in stool
  • To confirm diagnosis, test for function of suspected enzyme defect.

Management

There is no known cure for porphyria.

  • Prevent flares with strict avoidance of triggers (e.g., alcohol, sunlight).
  • Symptomatic treatment when flares occur:
    • Phlebotomy to remove porphyrins
    • Pain management Pain Management Pain is defined as an unpleasant sensory and emotional experience associated with actual or potential tissue damage. Pain is a subjective experience. Acute pain lasts < 3 months and typically has a specific, identifiable cause. Pain Management → NSAIDs, opioids Opioids Opiates are drugs that are derived from the sap of the opium poppy. Opiates have been used since antiquity for the relief of acute severe pain. Opioids are synthetic opiates with properties that are substantially similar to those of opiates. Opioid Analgesics
    • Vomiting → antiemetics Antiemetics Antiemetics are medications used to treat and/or prevent nausea and vomiting. These drugs act on different target receptors. The main classes include benzodiazepines, corticosteroids, atypical antipsychotics, cannabinoids, and antagonists of the following receptors: serotonin, dopamine, and muscarinic and neurokinin receptors. Antiemetics
    • Tachycardia → beta-blockers
    • Seizures Seizures A seizure is abnormal electrical activity of the neurons in the cerebral cortex that can manifest in numerous ways depending on the region of the brain affected. Seizures consist of a sudden imbalance that occurs between the excitatory and inhibitory signals in cortical neurons, creating a net excitation. The 2 major classes of seizures are focal and generalized. Seizures → antiepileptics
  • Acute attack: IV hemin → decreases heme biosynthesis

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Differential Diagnosis

  • Lead poisoning: leads to decreased hemoglobin synthesis. Symptoms of lead poisoning include nausea, vomiting, headaches, encephalopathy, and peripheral neuropathy. Treatment is aimed at decreasing lead levels with chelation.
  • Acute anemia Anemia Anemia is a condition in which individuals have low Hb levels, which can arise from various causes. Anemia is accompanied by a reduced number of RBCs and may manifest with fatigue, shortness of breath, pallor, and weakness. Subtypes are classified by the size of RBCs, chronicity, and etiology. Anemia: Overview: condition in which individuals have low hemoglobin levels. Symptoms include fatigue, shortness of breath, pallor, and weakness. Anemia may occur because of blood loss, decreased RBC production such as in iron deficiency, or increased RBC destruction such as in hemolysis. Management is aimed at improving hemoglobin levels and treating the underlying conditions.
  • Hepatitis B Hepatitis B Hepatitis B virus (HBV) is a partially double-stranded DNA virus, which belongs to the Orthohepadnavirus genus and the Hepadnaviridae family. Most individuals with acute HBV infection are asymptomatic or have mild, self-limiting symptoms. Chronic infection can be asymptomatic or create hepatic inflammation, leading to liver cirrhosis and hepatocellular carcinoma (HCC). Hepatitis B Virus and C: viral infections of the liver Liver The liver is the largest gland in the human body. The liver is found in the superior right quadrant of the abdomen and weighs approximately 1.5 kilograms. Its main functions are detoxification, metabolism, nutrient storage (e.g., iron and vitamins), synthesis of coagulation factors, formation of bile, filtration, and storage of blood. Liver that cause inflammation Inflammation Inflammation is a complex set of responses to infection and injury involving leukocytes as the principal cellular mediators in the body's defense against pathogenic organisms. Inflammation is also seen as a response to tissue injury in the process of wound healing. The 5 cardinal signs of inflammation are pain, heat, redness, swelling, and loss of function. Inflammation and damage of hepatocytes. The presentation of these 2 infections depends on whether the infection is acute or chronic, and it is specific to the type of hepatitis present. Diagnosis is established by detecting antibodies Antibodies Immunoglobulins (Igs), also known as antibodies, are glycoprotein molecules produced by plasma cells that act in immune responses by recognizing and binding particular antigens. The various Ig classes are IgG (the most abundant), IgM, IgE, IgD, and IgA, which differ in their biologic features, structure, target specificity, and distribution. Immunoglobulins or viral antigens in the serum. 
  • Hodgkin lymphoma Hodgkin lymphoma Hodgkin lymphoma (HL) is a malignancy of B lymphocytes originating in the lymph nodes. The pathognomonic histologic finding of HL is a Hodgkin/Reed-Sternberg (HRS) cell (giant multinucleated B cells with eosinophilic inclusions). The disease presents most commonly with lymphadenopathy, night sweats, weight loss, fever, splenomegaly and hepatomegaly. Hodgkin Lymphoma: malignancy of B lymphocytes B lymphocytes B lymphocytes, also known as B cells, are important components of the adaptive immune system. In the bone marrow, the hematopoietic stem cells go through a series of steps to become mature naive B cells. The cells migrate to secondary lymphoid organs for activation and further maturation. B Cells originating in lymph nodes. The disease presents most commonly with lymphadenopathy Lymphadenopathy Lymphadenopathy is lymph node enlargement (> 1 cm) and is benign and self-limited in most patients. Etiologies include malignancy, infection, and autoimmune disorders, as well as iatrogenic causes such as the use of certain medications. Generalized lymphadenopathy often indicates underlying systemic disease. Lymphadenopathy (neck most commonly involved), night sweats, weight loss, fever Fever Fever is defined as a measured body temperature of at least 38°C (100.4°F). Fever is caused by circulating endogenous and/or exogenous pyrogens that increase levels of prostaglandin E2 in the hypothalamus. Fever is commonly associated with chills, rigors, sweating, and flushing of the skin. Fever, and at times, splenomegaly Splenomegaly Splenomegaly is pathologic enlargement of the spleen that is attributable to numerous causes, including infections, hemoglobinopathies, infiltrative processes, and outflow obstruction of the portal vein. Splenomegaly and hepatomegaly. Hodgkin lymphoma Hodgkin lymphoma Hodgkin lymphoma (HL) is a malignancy of B lymphocytes originating in the lymph nodes. The pathognomonic histologic finding of HL is a Hodgkin/Reed-Sternberg (HRS) cell (giant multinucleated B cells with eosinophilic inclusions). The disease presents most commonly with lymphadenopathy, night sweats, weight loss, fever, splenomegaly and hepatomegaly. Hodgkin Lymphoma is managed with chemotherapy and radiotherapy.
  • Acute lymphoblastic leukemia Acute Lymphoblastic Leukemia Acute lymphoblastic leukemia/lymphoma (ALL/LBL) are hematologic malignancies characterized by the uncontrolled proliferation of lymphoid precursor cells. Acute lymphoblastic leukemia/lymphoma, the most common forms of cancer affecting children, show the presence of increased lymphoblasts. Acute Lymphoblastic Leukemia (ALL): hematologic malignancy that starts in the bone marrow Bone marrow Bone marrow, the primary site of hematopoiesis, is found in the cavities of cancellous bones and the medullary canals of long bones. There are 2 types: red marrow (hematopoietic with abundant blood cells) and yellow marrow (predominantly filled with adipocytes). Composition of Bone Marrow. Patients present with fatigue, pallor, bleeding, fever Fever Fever is defined as a measured body temperature of at least 38°C (100.4°F). Fever is caused by circulating endogenous and/or exogenous pyrogens that increase levels of prostaglandin E2 in the hypothalamus. Fever is commonly associated with chills, rigors, sweating, and flushing of the skin. Fever, and infection related to the anemia Anemia Anemia is a condition in which individuals have low Hb levels, which can arise from various causes. Anemia is accompanied by a reduced number of RBCs and may manifest with fatigue, shortness of breath, pallor, and weakness. Subtypes are classified by the size of RBCs, chronicity, and etiology. Anemia: Overview, thrombocytopenia Thrombocytopenia Thrombocytopenia occurs when the platelet count is < 150,000 per microliter. The normal range for platelets is usually 150,000-450,000/µL of whole blood. Thrombocytopenia can be a result of decreased production, increased destruction, or splenic sequestration of platelets. Patients are often asymptomatic until platelet counts are < 50,000/µL. Thrombocytopenia, and lack of functional WBCs seen in acute leukemia. Diagnosis is made with peripheral blood smear and bone marrow Bone marrow Bone marrow, the primary site of hematopoiesis, is found in the cavities of cancellous bones and the medullary canals of long bones. There are 2 types: red marrow (hematopoietic with abundant blood cells) and yellow marrow (predominantly filled with adipocytes). Composition of Bone Marrow biopsy findings.

References

  1. Bissell, D. M., Anderson, K. E., Bonkovsky, H. L. (2017). Porphyria. New England Journal of Medicine 377:862–872. https://www.nejm.org/doi/10.1056/NEJMc1712682
  2. Gounden V, Jialal I. (2020). Acute porphyria. In: StatPearls. https://www.ncbi.nlm.nih.gov/books/NBK537352/
  3. Gounden V, Jialal I. Acute porphyria. StatPearls. https://www.ncbi.nlm.nih.gov/books/NBK537352/

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