124: The Porphyrias Flashcards
What are the two main classifications of porphyrias based on the accumulation of heme precursors?
Porphyrias are classified as either hepatic or erythropoietic based on whether heme precursors first accumulate in the liver or bone marrow.
What distinguishes cutaneous porphyrias from acute porphyrias?
Cutaneous porphyrias are characterized by overproduction and accumulation of photosensitizing porphyrins, leading to chronic blistering and scarring on sun-exposed skin. In contrast, acute porphyrias are marked by neurologic symptoms and elevated levels of porphyrin precursors, such as d-aminolevulinic acid (ALA) and porphobilinogen (PBG).
What is the role of the enzyme ALAS in the heme synthesis pathway?
ALAS (Aminolevulinic Acid Synthase) is the first enzyme in the heme synthesis pathway. It combines glycine and succinyl-coenzyme A to produce the amino acid d-aminolevulinic acid (ALA), which is a precursor in the synthesis of heme.
How does the synthesis of heme occur in the body, and where does the majority take place?
Heme synthesis occurs in 8 steps, each catalyzed by a different enzyme. The majority (85%) of heme synthesis occurs in the bone marrow to support hemoglobin formation, with the remainder primarily in the liver for cytochrome P450 enzymes.
What is the significance of the enzyme ferrochelatase (FECH) in heme synthesis?
Ferrochelatase (FECH) is the final enzyme in the heme synthesis pathway. It is responsible for inserting iron into protoporphyrin IX to form heme, which is essential for the function of many hemoproteins, including hemoglobin.
What are porphyrias caused by?
Abnormalities of the 8 enzymes in the heme biosynthetic pathway.
How are porphyrias classified?
As hepatic or erythropoietic based on whether heme precursors accumulate in the liver or bone marrow.
What characterizes cutaneous porphyrias?
Overproduction and accumulation of photosensitizing porphyrins, causing chronic blistering and scarring on sun-exposed areas of skin.
What are acute porphyrias characterized by?
Neurologic symptoms and elevated levels of porphyrin precursors, d-aminolevulinic acid (ALA) and porphobilinogen (PBG).
What is the first enzyme in the heme synthesis pathway?
ALAS, which combines glycine and succinyl-coenzyme A to produce d-aminolevulinic acid (ALA).
What is the role of heme in the body?
Heme is the prosthetic group for many essential hemoproteins, including hemoglobin.
What is the final enzyme in heme synthesis?
Ferrochelatase (FECH).
What percentage of heme synthesis occurs in the bone marrow?
85%.
What regulates heme synthesis in the liver?
Primarily by the activity of d-aminolevulinic acid synthase 1 (ALAS1).
What is the most common type of porphyria and what are its key characteristics?
Porphyria cutanea tarda (PCT) is the most common porphyria, characterized by skin friability and chronic blistering lesions on sun-exposed areas, particularly the hands. It typically develops in mid- to late life and is associated with deficient uroporphyrinogen deaminase (UROD) activity in hepatocytes, leading to the accumulation of porphyrins. In active cases, hepatic UROD activity is reduced to less than 20% of normal.
What are the clinical features associated with porphyria cutanea tarda (PCT)?
Clinical features of PCT include:
1. Development in the fourth or fifth decade of life, most commonly in males.
2. Fluid-filled blisters and bullae on sun-exposed areas, especially the dorsal hands.
3. Eroded areas prone to bacterial infection, with residual scarring and pigmentation changes.
4. Facial hypertrichosis and hyperpigmentation may occur.
5. Severe thickening of skin resembling systemic sclerosis, termed pseudoscleroderma.
6. Neurologic symptoms characteristic of acute porphyrias are absent in PCT.
What susceptibility factors are associated with the development of porphyria cutanea tarda (PCT)?
Susceptibility factors for PCT include:
- Genetic factors
- Viral infections
- Chemical exposures
- Alcohol use (87% of patients)
- Smoking (81% of patients)
- Chronic hepatitis C (69% of patients)
- HFE (hematochromatosis) mutations (53% of patients)
These factors do not cause PCT by themselves but are often present in patients with the condition.
What is the significance of UROD mutations in porphyria cutanea tarda (PCT)?
UROD mutations are significant in PCT as follows:
- Most PCT patients have sporadic (type 1) disease.
- Approximately 20% have a heterozygous predisposing UROD mutation, classified as familial (type 2) PCT.
- Type 2 PCT is autosomal dominant with low penetrance and requires other susceptibility factors to develop.
- HEP (homozygous form of type 2 PCT) resembles congenital erythropoietic porphyria (CEP) clinically.
How does iron and hemochromatosis gene (HFE) mutations relate to porphyria cutanea tarda (PCT)?
Iron and HFE mutations relate to PCT as follows:
- Iron stores are usually normal or increased in PCT, while iron deficiency is protective.
- Iron creates an oxidative environment in hepatocytes, facilitating the generation of a UROD inhibitor.
- The C282Y mutation of the HFE gene is prevalent in PCT patients, with up to 20% being homozygotes, potentially leading to earlier onset of disease.
- HFE mutations impair sensing of serum iron, reducing hepatic hepcidin production, which affects iron absorption.
What role does alcohol play in the onset of porphyria cutanea tarda (PCT)?
Alcohol and its metabolites may predispose individuals to the onset of PCT by inducing hepatic ALAS1 and cytochrome P450 enzymes (CYPs), which generate reactive oxygen species (ROS). This oxidative stress can contribute to the development of PCT in susceptible individuals.
What is the most common type of porphyria?
Porphyria cutanea tarda (PCT).
What are the characteristic skin features of PCT?
Development of skin friability and chronic, blistering lesions on sun-exposed areas of the skin.
What enzyme deficiency is associated with PCT?
Deficient uroporphyrinogen deaminase (UROD) activity in hepatocytes.
What is the typical age of onset for PCT?
In the fourth or fifth decade of life, most commonly in males.
What are common susceptibility factors for developing PCT?
Genetic factors, viral infections, and chemical exposures, with ethanol use being the most common.
What is the response of PCT to treatment?
PCT responds well to either phlebotomy or low-dose hydroxychloroquine.
What are the common clinical features of PCT?
Fluid-filled blisters, erosion of skin, scarring, hyperpigmentation, and facial hypertrichosis.
What is the relationship between iron levels and PCT?
Iron stores are always normal or increased in PCT, whereas iron deficiency is protective.
What is the significance of UROD mutations in PCT?
Approximately 20% of patients have a heterozygous UROD mutation, but these do not cause PCT without other susceptibility factors.
How does alcohol consumption relate to PCT?
Alcohol and its metabolites may predispose to the onset of PCT by inducing hepatic ALAS1 and CYPs, generating ROS.
A patient presents with chronic blistering lesions on sun-exposed skin. What is the most common porphyria associated with these symptoms, and what is the first-line screening test?
The most common porphyria associated with chronic blistering lesions on sun-exposed skin is Porphyria Cutanea Tarda (PCT). The first-line screening test is total plasma or urine porphyrins.
What role does smoking play in the development of porphyria cutanea tarda (PCT)?
Smoking is regarded as an independent risk factor for PCT. It may increase oxidative stress in hepatocytes and induces hepatic CYPs, particularly CYP1A2, which is important for the development of uroporphyria in rodent models. Hepatic CYPs are often increased in human PCT, and a more inducible CYP1A2 variant is found to be more common in PCT than in normal subjects.
How does estrogen influence the risk of developing porphyria cutanea tarda (PCT)?
Estrogen use is common in women with PCT, and the disease has also occurred in some men treated with estrogen for prostate cancer. Female rats or males receiving estrogens are more susceptible to chemically-induced uroporphyria than untreated males, possibly due to the generation of reactive oxygen species (ROS).
What is the relationship between hepatitis C and porphyria cutanea tarda (PCT)?
Hepatitis C promotes hepatocyte steatosis, iron accumulation, mitochondrial dysfunction, oxidative stress, and dysregulation of hepcidin expression. The prevalence of chronic hepatitis C in PCT ranges from 21% to 92%, exceeding the prevalence of this viral infection in the general population. However, only 0.05% of individuals with chronic hepatitis C develop PCT.
What are the biochemical features associated with chemical exposure and drugs in the context of porphyria cutanea tarda (PCT)?
Outbreaks of PCT have been linked to exposure to chemicals such as hexachlorobenzene and 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). These chemicals cause biochemical features of PCT in laboratory animals and cultured hepatocytes, indicating a significant relationship between chemical exposure and the development of PCT.
What is the significance of UROD activity in the pathogenesis of porphyria cutanea tarda (PCT)?
PCT develops when hepatic UROD activity is reduced to approximately 20% of normal. With enzyme inhibition, the amount of UROD protein remains at its genetically determined level in the liver. About 20% of patients are heterozygous for UROD mutations, making them more susceptible to developing PCT due to reduced UROD activity in the liver.
What are the first-line tests for diagnosing porphyria cutanea tarda (PCT)?
The first-line testing for diagnosing PCT involves measuring total plasma or urine porphyrins. It is essential to establish a laboratory diagnosis of PCT before initiating treatment, especially since PCT can present with similar skin lesions as other types of porphyrias.
What is the role of total erythrocyte porphyrins in the diagnosis of PCT?
Total erythrocyte porphyrins are usually normal or modestly elevated in PCT. Markedly elevated levels may indicate rare cases of CEP, HEP, or homozygous HCP or VP, which typically present in infancy but can manifest in adults.
What factors should be assessed in patients with PCT regarding susceptibility?
Patients with PCT should be assessed for susceptibility factors such as:
- Alcohol and estrogen use
- Smoking
- Hepatitis C and HIV infection
- HFE and UROD mutations
These factors can influence the disease and its management.
What is the preferred treatment for PCT and how is it monitored?
The preferred treatment for PCT is phlebotomy to reduce hepatic iron. It is monitored by measuring serum ferritin levels, aiming for a target of 15 to 20 ng/mL. Phlebotomies are typically performed every two weeks, and the number of sessions required for remission is usually between 6 to 8.
What are the clinical implications of using hydroxychloroquine in PCT treatment?
A low-dose regimen of hydroxychloroquine is an effective alternative to phlebotomies in treating PCT. It mobilizes porphyrins accumulated in lysosomes and other intracellular organelles in hepatocytes without depleting hepatic iron, but full therapeutic doses can rapidly mobilize porphyrins and induce acute hepatitis.
How often are phlebotomies performed for PCT?
Phlebotomies are typically performed every two weeks.
How many phlebotomy sessions are usually required for remission in PCT?
The number of sessions required for remission is usually between 6 to 8.
What is the clinical implication of using hydroxychloroquine in PCT treatment?
A low-dose regimen of hydroxychloroquine is an effective alternative to phlebotomies in treating PCT.
What does hydroxychloroquine do in PCT treatment?
It mobilizes porphyrins accumulated in lysosomes and other intracellular organelles in hepatocytes without depleting hepatic iron.
What can full therapeutic doses of hydroxychloroquine induce?
Full therapeutic doses can rapidly mobilize porphyrins and induce acute hepatitis.
What is the significance of fluorescence scanning of diluted plasma in diagnosing porphyrias?
It helps to identify the porphyria most commonly misdiagnosed as PCT, which is VP, by detecting an emission peak at approximately 626 nm.
What urine test results are indicative of PCT?
A predominance of uroporphyrin, hepta-, hexa-, and pentacarboxyl porphyrins in urine.
What is the role of total erythrocyte porphyrins in diagnosing PCT?
They are normally or modestly elevated in PCT, but markedly elevated in rare cases of CEP, HEP, or homozygous HCP or VP.
Why is measuring serum ferritin important in PCT patients?
Serum ferritin should be measured as it may influence the choice of treatment and helps in monitoring the condition.
What treatment options are effective for PCT?
Phlebotomy or low-dose hydroxychloroquine is highly effective in both sporadic and familial forms of PCT.
What factors should be identified in PCT patients?
Patients should be questioned or examined for susceptibility factors such as alcohol and estrogen use, smoking, hepatitis C, HIV infection, and HFE and UROD mutations.
What is the recommended approach for managing elevated porphyrin levels in PCT?
Repeated phlebotomy to reduce hepatic iron is the preferred treatment, guided by serum ferritin levels.
What is the expected outcome after phlebotomy treatment in PCT patients?
Most patients require 6 to 8 phlebotomies for biochemical and clinical remission.
What should be monitored during phlebotomy sessions for PCT?
Measurement of hematocrit and ferritin at each session allows monitoring to prevent symptomatic anemia and assess progress toward the target ferritin level.
What is the potential consequence of resuming alcohol use in PCT patients?
Relapse of PCT may occur, often related to resumption of alcohol use, but usually responds to retreatment.
What is the recommended low-dose regimen for treating PCT?
A low-dose regimen of hydroxychloroquine 100 mg or chloroquine 125 mg (one half of a standard tablet) twice weekly is recommended.
What are the clinical features associated with hepatocutaneous porphyria (HEP)?
The clinical features of HEP include blistering skin lesions, hypertrichosis, scarring, hemolytic anemia, red urine, and sclerodermoid skin changes.
What is the significance of erythrocyte UROD activity in hepatocutaneous porphyria (HEP)?
In HEP, erythrocyte UROD activity is markedly diminished, typically ranging from 5% to 30% of normal.
What are the recommended therapies for patients with hepatocutaneous porphyria (HEP)?
Recommended therapies include avoiding sunlight, phlebotomy, hydroxychloroquine, oral charcoal in severe cases, and potential gene replacement therapy.
What are the clinical features of Hepatoerythropoietic Porphyria (HEP)?
Onset of blistering skin lesions, hypertrichosis, scarring, hemolytic anemia, and red urine typically in early childhood.
