Pathogenesis and clinical management of liver damage in porphyrias: Mechanisms and therapeutic approaches

Abstract

Porphyria refers to a group of rare inherited metabolic disorders caused by enzymatic deficiencies in the heme biosynthesis pathway. These deficiencies lead to the pathological accumulation of neurotoxic porphyrin precursors, resulting in multisystem damage. Currently, there are no curative therapeutic interventions, and patients frequently experience severe morbidity or life-threatening complications. Among the most critical manifestations is protoporphyric liver disease, in which hepatotoxic porphyrins and their precursors drive progressive hepatic injury and cholestasis. Persistent elevation of these metabolites can lead to irreversible parenchymal damage, significantly affecting both quality of life and long-term prognosis. The clinical presentation of porphyria-associated liver injury is highly variable and often has an insidious onset. However, a subset of patients may experience rapid progression to acute liver failure or fulminant hepatic dysfunction. Diagnosis is based on clinical evaluation and is confirmed by genetic testing. Current treatment strategies are focused on symptom management while underlying disease mechanisms remain unaddressed, posing significant therapeutic challenges. This review summarizes the pathophysiology, clinical manifestations, and diagnostic approaches for porphyria-associated liver injury, highlighting emerging therapies with the potential to improve patient outcomes.

Key Words: Porphyria; Porphyria-related liver injury; Pathophysiology; Hepatic cutaneous porphyrias; Protoporphyria; Acute hepatic porphyrias

Core Tip: Porphyria-related liver injury, driven by toxic accumulation of heme biosynthesis intermediates, presents diagnostic challenges due to nonspecific symptoms and insidious progression. The "Two-Hit Model" (porphyrin-protein aggregation and oxidative stress) underpins hepatotoxicity, while protoporphyria-associated cholestasis, liver failure, and acute hepatic porphyria-linked hepatocellular carcinoma (HCC) further increase morbidity. Diagnosis follows a multistep process integrating biochemical profiling, histopathological examination, and genetic testing. Current therapies are palliative, whereas emerging approaches—such as RNA interference (givosiran), melanocortin agonists (afamelanotide), and gene-editing technologies—provide mechanistic targeting. Early surveillance for HCC and multidisciplinary management are essential to mitigate life-threatening complications in these rare metabolic disorders.

INTRODUCTION

Porphyria encompasses a spectrum of metabolic disorders arising from defective enzymatic activity within the heme biosynthesis pathway, which are primarily hereditary in origin[1]. Heme, an iron-containing porphyrin, serves as an essential cofactor for proteins such as hemoglobin, myoglobin, cytochrome P450, catalase, and peroxidase[2]. It is synthesized de novo from glycine and succinyl-CoA through a series of reactions catalyzed by eight specific enzymes, encoded by nine genes; defects in these enzymes correspond to the eight distinct porphyrias[3]. The affected enzymatic steps classify these disorders and include X-linked protoporphyria (XLP), δ-aminolevulinic acid (ALA) dehydratase (ALAD) deficiency porphyria (ADP), acute intermittent porphyria (AIP), congenital erythropoietic porphyria (CEP), porphyria cutanea tarda (PCT), hereditary coproporphyria (HCP), variegate porphyria (VP), and erythropoietic protoporphyria (EPP; Figure 1). Approximately 85% of heme synthesis occurs in the bone marrow for the production of hemoglobin. In comparison, approximately 15% occurs in the liver for P450 hemoprotein synthesis, both of which are major sites of pathology in porphyria[4,5]. Consequently, porphyrias are divided into hepatic and erythropoietic types. Hepatic porphyrias are further divided into acute hepatic porphyrias (AHPs), including AIP, ADP, HCP, and VP, and chronic hepatic porphyrias, exemplified by PCT. Erythropoietic porphyrias include EPP, XLP, and CEP. Additionally, porphyrias can be classified by clinical presentation into acute hepatic or cutaneous types.

Figure 1 Metabolic pathway of porphyrias and associated disorders: Key enzymes. Intermediates and disease subtypes. ALA: Δ-aminolevulinic acid; AIP: Acute intermittent porphyria; ADP: Δ-aminolevulinic acid dehydratase deficiency porphyria; EPP: Erythropoietic protoporphyria; VP: Variegate porphyria; PCT: Porphyria cutanea tarda; HEP: Hepatoerythropoietic porphyria; HCP: Hereditary coproporphyria. This figure was created using FigDraw (Supplementary material; www.figdraw.com).

Enzymatic deficiencies result in the accumulation of intermediates in tissues, which can lead to cellular damage. Elevated porphyrin concentrations give rise to diverse clinical manifestations, ranging from acute neurologic crises—characterized by severe abdominal pain and neuropsychiatric disturbances—to dermatological findings, such as bullous eruptions and photosensitive dermatitis in areas exposed to ultraviolet light[6].

The rarity and varied presentations of porphyria, which can mimic other systemic diseases, often result in low clinical awareness and prolonged diagnostic delays[7,8]. Currently, no curative treatment exists for porphyria, and it can result in significant long-term sequelae. These complications, varying by subtype, include hepatic dysfunction, hepatocellular carcinoma (HCC), acute liver failure, chronic pain, fatigue, psychiatric disorders, porphyria-associated nephropathy (chronic kidney disease and renal failure), hypertension, osteoporosis, vitamin D deficiency, anemia, and non-hepatic malignancies[9]. Notably, protoporphyria-associated liver disease is among the most severe complications of porphyria, with pathogenesis closely linked to the hepatotoxicity of porphyrins and their precursors[10].

As a major metabolic organ, the liver plays a critical role in synthesizing and metabolizing porphyrins and their precursors. Sustained high concentrations of these substances lead to variable liver injury and cholestasis, significantly impairing patients’ quality of life and prognosis. This condition often serves as a key clinical indicator, prompting evaluation[11]. Clinical manifestations of porphyria-related liver injury are variable and often insidious. In some patients, disease progression may rapidly advance to acute or fulminant liver failure[12,13]. Current therapies remain limited to symptom management without addressing the underlying pathophysiology, presenting a significant challenge in managing porphyria-associated liver disease.

Despite diagnostic advances, early detection of porphyria remains challenging due to insidious progression and complex clinical presentation. Traditional treatments focus on symptom relief but fail to address the underlying pathological processes effectively. Currently, no curative treatment is available for porphyria-related liver damage. This article provides a comprehensive review of the pathophysiological mechanisms, clinical manifestations, and therapeutic strategies for porphyria-related liver damage.

EPIDEMIOLOGY

The rarity and insidious onset of porphyrias result in widely varying prevalence estimates, largely reflecting differences in study methodologies and the inclusion of latent vs symptomatic cases. Geographic and ethnic variation, coupled with diagnostic inconsistencies, further complicates the accurate assessment of prevalence, underscoring the need for comprehensive epidemiological studies. Among the various types of porphyrias, PCT, AIP, and EPP are the most prevalent. Of these, PCT has the highest prevalence, estimated at 1 per 10000 individuals globally[14], approximately 1 in 25000 symptomatic cases in the United States[15], up to 1 in 5000 in the Czech Republic and Slovakia[16], and approximately 1 in 100000 in Norway[17]. The combined prevalence of symptomatic AHPs is estimated at 5-10 per 100000 individuals, though this figure may be underestimated[18]. Among AHPs, AIP is the most common subtype. Characterized by low penetrance and significant heterogeneity, AIP exhibits considerable variability in prevalence across different studies[19]. The prevalence of symptomatic AIP ranges from 5.5 to 192 cases per million individuals, whereas the frequency of pathogenic HMBS mutations in the general population is estimated to be 1 in 1299 to 1 in 10000[20]. Notably, the penetrance of AIP in the general population has been reported to range from < 1% to 42%[20]. EPP is the most common childhood porphyria, with incidence rates of 1 in 180000 in Sweden, 1 in 152000 in South Africa, 1 in 200000 in the United Kingdom, 1 in 79000 in Northern Ireland, and 1 in 75000 in the Netherlands[21-24]. In Europe, the incidence of EPP is reported to be 0.12 new cases per million inhabitants annually, with a prevalence of 9.2 cases per million inhabitants[25]. According to a porphyria study, the prevalence of EPP in Israel is 1.6 cases per million inhabitants[26]. Other porphyria subtypes are considerably rarer, and epidemiological data remain scarce.

In China, epidemiological data remain limited. An analysis of the ChinaMAP database estimated carrier frequencies for AIP (1/1059), HCP (1/1513), VP (1/10588), PCT (1/1765), ADP (1/5294), EPP (1/2117), hepatoerythropoietic porphyria (HEP; 1/1765), and CEP (1/2647), with predicted prevalence rates of 8.92 × 10^-9 for ADP, 7.51 × 10^-5 for EPP, 8.02 × 10^-8 for HEP, and 3.57 × 10^-8 for CEP[27]. A 10-year surveillance study conducted in 32 tertiary hospitals in Hebei Province reported annual AIP incidence rates of 0.03-0.05 per million between 2011 and 2017, increasing to 0.07-0.08 per million after 2018, with a consistent female predominance[28]. These findings indicate a distinctive genetic and epidemiological profile of porphyria in the Chinese population.

PATHOGENESIS OF LIVER DAMAGE IN PORPHYRIAS

The liver, as the body’s main metabolic organ, is the central hub for porphyrin metabolism. Abnormalities in this process can lead to the deposition of porphyrins and their precursors in the liver. When accumulated at high concentrations, these hepatotoxic substances can cause liver injury, cholestasis, bile duct stones, and progressive cirrhosis. The metabolic disturbances and liver manifestations of porphyrias vary by subtype (see Table 1). Moreover, patients with porphyrias have a significantly higher risk of HCC and cholangiocarcinoma than the general population. Therefore, liver involvement is a common complication of porphyrias, especially in PCT, VP, and EPP.

Table 1 Classification, genetic basis, and clinical features of major porphyria subtypes.

Porphyria type	Enzyme deficiency	Gene	Inheritance	Primary site of synthesis	Accumulated porphyrin intermediate	Neurovisceral symptoms	Cutaneous symptoms	Liver involvement
Acute hepatic porphyrias
ADP	ALA-dehydratase	ALAD	AR	Liver	ALA	+	-/+	-
AIP	PBG deaminase	HMBS	AD	Liver	ALA, PBG	++	-	-
HCP	Coproporphyrinogen oxidase	COPROX	AD	Liver	ALA, PBG, coproporphyrin III	+	+	-
VP	Protoporphyrinogen oxidase	PROTOX	AD	Liver	ALA, PBG, coproporphyrin III, protoporphyrin IX	+	+	+
Hepatic cutaneous porphyrias
PCT	Uroporphyrinogen decarboxylase	UROD	AD/sporadic	Liver	Urinary porphyrins, carboxylated porphyrin	-	++	+
HEP	Uroporphyrinogen decarboxylase	UROD	AR	Liver	Urinary porphyrins, carboxylated porphyrin	-	++	+
Erythropoietic cutaneous porphyrias
CEP	Uroporphyrinogen III synthase	UROS	AR	Bone marrow	Urinary porphyrin 1, fecal porphyrin I	-	++	-
EPP	Ferrochelatase	FECH	AR	Bone marrow	Protoporphyrin IX	-	++	+
XLP	ALA synthase 2	ALAS2	X-linked	Bone marrow	Protoporphyrin IX, Zn-bound protoporphyrin IX	-/+	+	+

AD: Autosomal dominant; AR: Autosomal recessive; ALA: Δ-aminolevulinic acid; PBG: Porphobilinogen; EPP: Erythropoietic protoporphyria; XLP: X-linked protoporphyria; AIP: Acute intermittent porphyria; UROD: Uroporphyrinogen decarboxylase.

Hepatocytes secrete excess protoporphyrin into bile and enter the enterohepatic circulation. As a hydrophobic compound, protoporphyrin is neither filtered by the kidneys nor soluble in bile[29]. This property disrupts the physiological balance between phospholipids, bile acids, and cholesterol, inducing cholestasis and causing structural changes in the hepatobiliary system that promote the formation of bile duct stones[30]. These pathological changes range from mild inflammation to fibrosis, cirrhosis, liver failure, and HCC. The effects of porphyrins and their metabolic intermediates on hepatocytes, as well as their link to liver diseases, remain poorly understood. Currently, porphyrin-mediated liver injury is best described by the Two-Hit Model[10].

The first "hit" involves the binding of porphyrin molecules to specific proteins, leading to the destabilization or unfolding of the protein’s local structure. This mainly occurs via non-covalent interactions—hydrophobic forces, electrostatic attractions, and hydrogen bonds—forming porphyrin–protein complexes that prime for protein aggregation[31]. The structural features of porphyrins enable direct binding to specific intracellular proteins, promoting protein aggregation. In cellular models and purified protein systems, porphyrins have been shown to form stable aggregates with cytoskeletal proteins, such as intermediate filaments, and other key proteins, including ER chaperones and proteasome subunits[32,33].

The second “hit” stems from endogenous triggers, including oxidative stress and inflammation, exemplified by macrophage infiltration or Kupffer cell activation. These stimuli generate reactive oxygen species (ROS), which then oxidize specific protein residues, further driving protein aggregation. Although porphyrins generate ROS via type I or II photosensitization under light—causing lipid peroxidation and protein oxidation—growing evidence indicates significant oxidative stress, even in the dark[33].

Studies have demonstrated that porphyrins preferentially bind to oxidized proteins, forming more stable aggregates that lead to cellular dysfunction and organ damage[31]. This model is supported by research in HCC cells, where hydrogen peroxide, generated by glucose oxidase, was used as an oxidant. Even in the dark, the combination of ALA and deferoxamine (DFO) with glucose oxidase induced marked protein aggregation, while ALA or DFO alone had minimal effects[31]. Furthermore, in the 3,5-diethoxycarbonyl-1,4-dihydrocollidine-induced mouse model of liver injury, substantial protein aggregation was observed, even under controlled light conditions, indicating that photosensitivity is not a prerequisite for porphyrin-induced visceral damage. Instead, oxidative stress and the interaction between porphyrins are the key drivers of damage[34].

DIAGNOSTIC APPROACH TO PORPHYRIA-ASSOCIATED LIVER INJURY

Diagnosis of porphyria-associated liver injury requires a structured, multi-step protocol that combines clinical assessment, biochemical profiling, histopathology, and genetic testing. This systematic protocol aims to reduce diagnostic delays and optimize subtype classification (Figure 2).

Figure 2 Diagnostic algorithm for porphyria-related liver injury. WES: Whole exome sequencing; PPBGD: Porphobilinogen deaminase; UROD: Uroporphyrinogen decarboxylase.

Step 1: Clinical recognition and suspicion criteria

Clinical suspicion is prompted by the following hallmark signs: Cutaneous photosensitivity (e.g., bullae or erythema in sunexposed areas), severe abdominal pain with paradoxical constipation and few physical signs, and neuropsychiatric symptoms from peripheral neuropathy to autonomic dysfunction (tachycardia, hypertension) or psychiatric disturbances (anxiety, hallucinations). Unexplained cholestasis, hepatomegaly, or elevated transaminases in the context of multisystem involvement should raise further suspicion.

Step 2: Exclusion of phenocopies

Porphyria must be differentiated from mimics—lead poisoning, tyrosinemia type I, systemic lupus erythematosus, and neurological disorders (e.g., Guillain-Barré syndrome)—by excluding alternative etiologies. This involves imaging to exclude structural abdominal pathology, serological testing to rule out autoimmune or infectious causes, and assessment of toxin exposure.

Step 3A: Histopathological evaluation

Histopathological assessment is crucial for diagnosing porphyriaassociated liver injury, especially when specialized biochemical porphyrin profiling is not available. Distinctive porphyrin deposition patterns define the hepatic pathology of protoporphyria. Histologically, brown–yellow protoporphyrin aggregates are present in bile canaliculi and hepatocytes (Figure 3A), confirming the hepatotoxic effects of accumulated intermediates. Under polarized light, Maltese cross-shaped birefringent crystals (Figure 3B and C) are pathognomonic, reflecting the crystalline structure of protoporphyrin–lipid complexes. In addition to protoporphyrin deposition, hepatic iron overload is prominent in some cases of EPP. Prussian blue staining shows granular iron deposits in hepatocytes and sinusoidal macrophages (Figure 3D), possibly due to secondary iron dysregulation or genetic predispositions (e.g., HFE mutations). The presence of protoporphyrin crystals or iron deposits on histology should prompt immediate progression to Step 4 for confirmation of the subtype.

Figure 3 Histopathological features of protoporphyria-associated liver injury. A: Hematoxylin and eosin staining shows brown-yellow protoporphyrin deposits within canaliculi and hepatocytes; B and C: Polarized light microscopy reveals Maltese cross-shaped birefringent crystals (blue arrows), indicative of protoporphyrin aggregation; D: Prussian blue staining highlights granular iron deposits (blue arrows).

Step 3B: Biochemical stratification (if available)

Most hospitals currently lack the capacity for routine biochemical screening of porphyrin-specific intermediates; however, biochemical profiling in specialized centers can further refine the classification of subtypes. AHPs are characterized by elevated urinary levels of ALA and porphobilinogen (PBG). Subtype patterns include the following: ADP with elevated urinary ALA and coproporphyrin III plus erythrocyte zinc-protoporphyrin IX (PPIX); AIP with markedly elevated urinary ALA, PBG, and uroporphyrin III; HCP with elevated urinary ALA, PBG, and coproporphyrin III and fecal coproporphyrin III predominance; and VP with urinary ALA/PBG spikes during acute attacks. In chronic hepatic porphyria, PCT is marked by elevated urinary uroporphyrin III in addition to increased fecal isocoproporphyrin. In CEP, Uro I and Copro I accumulate in the urine, feces, and erythrocytes. In contrast, EPP and XLP are distinguished by increased fecal PPIX: EPP shows erythrocyte-free proto IX predominance, and XLP shows zinc-bound proto IX predominance (Table 1).

Step 4: Molecular confirmation and integration of genotype and phenotype

Genetic testing provides definitive subtyping through targeted analysis of genes, including HMBS (AIP), FECH (EPP), and CPOX (HCP). Multigene panels or wholeexome sequencing can resolve complex cases, while functional assays clarify variants of uncertain significance. Integrating genetic data with clinical and biochemical findings enables precise diagnosis, guides therapeutic decisions (e.g., avoiding hepatotoxic drugs in VP), and supports family screening.

HEPATIC CUTANEOUS PORPHYRIAS

Hepatic cutaneous porphyrias include PCT and HEP, both of which are caused by uroporphyrinogen decarboxylase (UROD) deficiency, the fifth enzyme in the heme synthesis pathway[35,36]. UROD deficiency impairs uroporphyrinogen III decarboxylation, causing the accumulation of uroporphyrinogen III and its intermediates[35]. Under iron overload and oxidative stress, cytosolic uroporphyrinogen is oxidized into uroporphyrin. HEP is much rarer than PCT, with < 50 cases reported globally to date[37]. PCT is subdivided into sporadic (type 1) and familial (type 2) forms, depending on the UROD gene mutation status.

Sporadic (type 1) PCT is associated with the absence of UROD gene mutations. In contrast, familial (type 2) PCT involves heterozygous or homozygous UROD mutations, with symptoms manifesting once enzyme activity falls below 20% of normal[38]. Approximately 80% of PCT cases are sporadic, and only 20% involve UROD mutations, classifying PCT as chiefly acquired. Even familial mutations reduce UROD activity by only approximately 50%, necessitating additional triggers for symptom onset[15]. The susceptibility factors for PCT include alcohol consumption, smoking, hepatitis C virus (HCV) infection, human immunodeficiency virus (HIV) infection, estrogen use, and HFE mutations[39,40].

Clinical presentation

PCT manifests mainly with cutaneous symptoms and a chronic relapsing–remitting course, which differentiates it from other cutaneous porphyrias. PCT typically presents after the age of 40, primarily affecting the skin and liver. Skin lesions present as painful hemorrhagic blisters or clear vesicles on sun-exposed areas, often resulting in scarring and hyperpigmentation. Plasma and urine porphyrin profiles show characteristic patterns[41]. Compared to PCT, HEP skin lesions are usually more severe and persistent than those in PCT. HEP manifests in infancy or childhood with hematological abnormalities and severe photosensitivity[42].

Plasma porphyrin levels are elevated in PCT (normal < 1.0 μg/dL). Fluorescence analysis of plasma porphyrins typically shows a distinctive peak around 620 nm, which aids in differentiating PCT from VP and EPP[41]. Urinary porphyrins (normal < 300 μg/L) and fecal coproporphyrin levels are also elevated. Beyond photosensitive dermatitis, liver involvement is a key clinical feature of PCT. Over 60% of patients with PCT exhibit elevated transaminases, with hepatic dysfunction presenting as nonspecific symptoms, such as anorexia, abdominal distension, and ascites[43,44]. Ultrasound imaging in PCT often reveals multiple hyperechoic nodules in the liver; these are potentially related to focal fat deposition and can mimic malignant tumors, thereby posing significant diagnostic challenges[43]. Approximately 80% of patients with PCT have hepatic iron deposits on biopsy and elevated serum iron levels[45]. While hepatic iron plays a key role in the pathogenesis of PCT, the mechanisms underlying iron overload remain unclear, as conditions such as hemochromatosis do not predispose to PCT. On the other hand, phlebotomy to deplete iron stores can lead to clinical and biochemical remission, whereas iron supplementation may result in relapse[46]. Additionally, liver histopathology reveals the deposition of uroporphyrin and heptacarboxylic porphyrin in the liver, which display characteristic birefringent inclusions under polarized light microscopy[37]. Unfixed sections under Wood’s lamp exhibit intense red fluorescence, along with variable iron deposition, steatosis, focal necrosis, and periportal fibrosis[15,37].

HCC has long been recognized as a potential long-term complication of PCT. Substantial evidence implicates PCT as a key risk factor for HCC and cholangiocarcinoma[47-49]. A large Danish cohort (1989-2012) of patients with PCT was compared with matched population controls[50]. The 20-year survival rate for patients with PCT was 60.5%, which was significantly lower than that of the controls. Excess mortality in patients with PCT was mainly due to intestinal, hepatobiliary, and lung cancers[50]. A nationwide cohort study from Norway further supported these findings, reporting a significantly higher risk of HCC and biliary tract cancers among patients with PCT, with adjusted hazard ratios of 19.7 and 6.8, respectively[51]. However, unlike acute porphyrias, PCT is often complicated by coexisting risk factors, such as chronic alcohol use and HCV infection, which may confound the observed associations. Indeed, one study reported that 92% of patients with PCT had three or more concurrent risk factors[52]. Consequently, establishing a causal link between PCT and HCC remains challenging. Moreover, some studies suggest that the risk of HCC in PCT may be lower than previously thought[53]. These findings underscore the need for further research to elucidate the mechanistic links between PCT and HCC, while accounting for the influence of potential confounders.

Current therapies

Trigger avoidance is the cornerstone of PCT management. Patients should minimize sun exposure, apply sunscreen, avoid smoking and alcohol, and treat underlying HCV or HIV infections. Multiple studies have linked HCV and HIV infections with PCT[49,54-56]. Although the precise mechanisms remain unclear, antiHCV therapy significantly improves symptoms and porphyrin levels in PCT, thereby enhancing cure rates[56]. For patients with HIV infection, optimizing HIV management should be prioritized before initiating treatment for PCT. Additionally, individuals who are susceptible to exogenous triggers should avoid them. The use of medications that may exacerbate the condition should be avoided, particularly oral contraceptives, estrogen therapy, and oral iron supplements[46,57].

Phlebotomy is considered an effective first-line treatment for PCT, as it interrupts the production of iron-dependent uroporphyrin inhibitors in hepatocytes[40]. A typical regimen involves removing 450 mL of blood biweekly, which minimizes the risk of anemia. However, whether this approach improves liver function remains unclear. Additionally, 4-aminoquinolines, such as chloroquine (CQ) or hydroxychloroquine (HCQ), are also widely used as first-line therapies and are believed to have similar efficacy to phlebotomy[58]. Phlebotomy and low-dose HCQ are established first-line therapies for PCT. A pilot RCT (NCT01573754) of 48 patients with PCT compared phlebotomy with HCQ 100 mg twice weekly, showing a median remission of 6.9 months vs 6.1 months, with similar safety profiles. HCQ demonstrated superior compliance and cost-effectiveness, supporting its use as a first-line alternative to phlebotomy; however, non-inferiority was not formally established. Although the precise mechanisms of CQ/HCQ in porphyrin remain uncertain, the most accepted hypothesis is that these agents bind to porphyrins in hepatocytes, facilitating their excretion through urine[59].

PROTOPORPHYRIA

Protoporphyria is a metabolic disorder characterized by the accumulation of PPIX in erythrocytes, resulting from defects in the heme biosynthesis pathway[60]. This condition is classified into three distinct types: EPP, XLP, and CLPX-protoporphyria, each associated with mutations in the FECH, ALAS2, and CLPX genes, respectively[61-63]. EPP accounts for the majority of cases, representing over 90% of individuals affected by protoporphyria, while XLP and CLPX-protoporphyria are less prevalent[61]. PPIX is primarily produced in the bone marrow (approximately 85%), followed by the liver (approximately 15%) through the heme biosynthesis pathway[24]. As a photosensitizing agent, elevated levels of PPIX in the skin can lead to activation upon exposure to visible light, particularly blue light, generating ROS, such as singlet oxygen[64]. These ROS can damage cell membranes, proteins, and DNA, resulting in phototoxic reactions that manifest as pain, erythema, swelling, and, in severe cases, blistering of the skin[11].

Clinical presentation

A hallmark clinical feature of protoporphyria is the onset of painful photosensitivity from an early age, typically affecting the face, the dorsal aspects of the hands and feet, and the forearms[65]. Initial prodromal symptoms include itching, stinging, and burning sensations. Depending on the intensity of sunlight exposure, this pain can persist for several hours to days. The age of onset is typically early, usually presenting before the age of 5, with retrospective studies indicating a median onset between 1 and 3 years[61]. Prolonged exposure to sunlight can lead to erythema and edema. In addition to painful photosensitivity, patients with protoporphyria may experience various complications, including hepatobiliary diseases, anemia, vitamin D deficiency, and osteoporosis[66].

Hepatobiliary complications are frequently observed in clinical practice, commonly presenting as hepatic dysfunction and cholelithiasis. Currently, liver and biliary diseases caused by EPP are generally classified into four stages: Cholelithiasis, mild liver disease, deteriorating liver disease, and the terminal phase of EPP-associated liver disease[67]. PPIX, a hydrophobic porphyrin compound, undergoes primary hepatic elimination and is subsequently excreted into the bile. A proportion of excreted PPIX undergoes intestinal reabsorption, facilitating its return to the liver through enterohepatic recirculation[64]. Elevated concentrations of PPIX may precipitate crystalline deposition, leading to stone formation within the biliary tract[64]. This process contributes to cholestatic injury and hepatocellular damage. With cholelithiasis occurring in up to 23.5% of cases of EPP, it should be considered in the differential diagnosis, especially in pediatric patients[68].

Mild liver disease is more prevalent in patients with protoporphyria and is often asymptomatic. Clinical manifestations typically include isolated biochemical abnormalities, such as elevated liver enzymes, notably transaminases, alkaline phosphatase, and γ-glutamyl transferase. Retrospective studies suggest that > 30% of patients with EPP exhibit transient or persistent transaminase elevation, with PPIX levels significantly higher in those with hepatic dysfunction[68].

Hepatocellular damage further affects porphyrin metabolism and impairs porphyrin excretion, leading to progressive liver dysfunction in some patients. As liver function deteriorates, clinical symptoms, such as jaundice and abdominal pain, may emerge. When jaundice becomes clinically evident, it often indicates significant hepatic injury. Physical examination may reveal splenomegaly, and some patients may develop acute pancreatitis. Severe hepatobiliary complications, including acute liver failure (referred to as "EPP hepatic crisis"), occur in 1%-5% of cases[67]. These individuals frequently progress to end-stage cholestatic liver disease, which is often fatal, necessitating orthotopic liver transplantation as definitive management[52,69,70]. EPP is frequently associated with iron metabolism disorders, with 20%-60% of patients presenting with anemia, primarily characterized by microcytosis and hypochromia[11,71,72]. However, iron supplementation in patients with EPP requires caution, as iron can increase ALA activity, exacerbating the accumulation of PPIX in erythrocytes and the liver. Additionally, due to prolonged sun avoidance, patients with EPP often experience vitamin D deficiency, which can lead to subsequent osteoporosis[73,74].

Current therapies

Preventing phototoxic exposure (such as sun avoidance, protective clothing, sunglasses, and physical sunscreens), alleviating pain (such as analgesics), and maintaining good psychological health (through counseling) are the fundamental preventive and management strategies.

Treatment of phototoxic skin injury

The only agent currently proven effective and approved for treating phototoxicity in EPP is afamelanotide, a synthetic tridecapeptide structural analog of α-melanocyte-stimulating hormone (α-MSH), which functions as a first-in-class agonist of the MC1R[75]. Endogenous α-MSH regulates melanocyte activity to enhance epidermal melanin synthesis and exhibits anti-inflammatory and immunomodulatory properties[76]. Current phase III trial data indicate that afamelanotide can prolong the duration of pain-free exposure to direct sunlight, reduce the frequency of phototoxic reactions, and significantly improve the quality of life for patients[77]. Afamelanotide does not affect porphyrin production, and patients generally tolerate it well. It is typically administered during the summer months or when increased sun exposure is expected, with a subcutaneous injection of 16 mg of afamelanotide in a slow-release implant every 2 months[75]. Other agents, including high-dose β-carotene, vitamin C, and N-acetylcysteine, have been proposed to mitigate the pathogenic effects of PPIX by scavenging ROS; however, existing studies have yielded inconsistent results, with considerable variability in study quality[78]. Current evidence remains insufficient to establish the efficacy of these treatments in managing EPP.

Treatment of liver injury

Ursodeoxycholic acid (UDCA) improves bile flow, alleviates cholestasis, and exhibits anti-inflammatory effects by suppressing hepatic inflammation and reducing hepatocyte damage[79]. Additionally, UDCA enhances the stability of hepatocyte membranes, thereby mitigating oxidative stress and apoptosis[79]. Case reports suggest that UDCA may be beneficial in the management of late-stage liver disease in patients with EPP, although its precise role remains a topic of debate[80]. Cholestyramine and activated charcoal can reduce intestinal protoporphyrin levels by interrupting the enterohepatic circulation, potentially offering therapeutic benefits for patients with EPP[81-84].

Therapeutic plasma exchange has proven to be a rapid and effective treatment for protecting the liver by rapidly reducing plasma levels of PPIX, thereby mitigating PPIX-induced hepatic injury[11,85]. A similar approach, red cell exchange, involves the partial replacement of the patient's red blood cells[13]. Since the concentration of protoporphyrin in red blood cells is much higher than in plasma, removing red blood cells with elevated protoporphyrin levels and replacing them with healthy donor red blood cells can lower the overall protoporphyrin levels in the patient's blood. However, the effectiveness of this treatment remains uncertain[66,86]. Similarly, infusions of heme or red blood cells aimed at suppressing erythropoiesis may help reduce PPIX production[66]. Nevertheless, the risks associated with blood transfusions, such as circulatory overload, immune transfusion reactions, and iron overload, must be carefully weighed and considered.

For patients with advanced liver disease, the aforementioned treatments are often used as a "bridge" to liver transplantation, with the primary goal of alleviating the burden of excess PPIX in the body. Liver transplantation remains the only effective treatment for improving liver function; however, it does not address the ongoing production of excess PPIX in the circulation, meaning it cannot cure the disease. Reports indicate that 65%-80% of patients experience recurrent EPP-related liver disease after transplantation[83]. The recurrence of protoporphyria-associated liver disease post-transplant is a significant challenge. Sequential bone marrow transplantation following liver transplantation may have potential in reducing post-transplant recurrence[87].

ACUTE HEPATIC PORPHYRIAS

AHPs encompass a group of rare genetic disorders characterized by aberrations in the heme biosynthesis pathway due to mutations in hepatic heme-synthesizing enzymes. This group includes four distinct types: AIP, HCP, VP, and ADP. Notably, while ADP follows an autosomal recessive inheritance pattern, the other three types are autosomal dominant disorders[88]. The rate-limiting enzyme in heme biosynthesis is δ-aminolevulinate synthase, which catalyzes the initial step of heme synthesis—the condensation of glycine and succinyl-CoA to form ALA. ALA is subsequently converted to PBG by ALA dehydratase. AHPs share a common pathophysiological mechanism: Decreased heme production leads to a loss of negative feedback inhibition on ALAS, resulting in its upregulation and a compensatory accumulation of ALA and PBG[89-91]. A hallmark feature of AHPs is the excessive accumulation of these neurotoxic porphyrin precursors, which underlie the predominant neurological manifestations observed in affected individuals[92]. AIP is the most prevalent form of AHP. It results from a deficiency of HMBS (also known as PBG deaminase), the third enzyme in the porphyrin synthesis pathway, with more than 500 disease-associated variants reported to date[91]. Reduced HMBS activity impairs the metabolism of ALA and PBG, leading to their pathological accumulation in the blood, urine, and tissues. Clinically, AIP is characterized by episodic abdominal pain, neurological symptoms, and psychiatric disturbances.

VP is caused by mutations in the PPOX gene, which encodes protoporphyrinogen oxidase, the penultimate enzyme in the heme biosynthesis pathway. PPOX catalyzes the conversion of protoporphyrinogen IX to PPIX[93].

HCP arises from mutations in the CPOX gene, which encodes coproporphyrinogen oxidase, the sixth enzyme in the heme biosynthesis pathway. CPOX catalyzes the conversion of coproporphyrinogen III to protoporphyrinogen IX. In contrast to AIP, the elevation of ALA and PBG is less pronounced in HCP[94]. Notably, both VP and HCP can present with neurovisceral symptoms as well as cutaneous photosensitivity.

ADP, the rarest form of AHP, has been reported in only a few cases to date[95]. ADP results from mutations in the ALAD gene, which encodes ALAD, the second key enzyme in heme biosynthesis. ALAD catalyzes the condensation of two ALA molecules to form PBG[95].

Clinical presentation of AHPs

Compared to protoporphyria, AHPs typically manifest later in life, with most cases occurring after puberty. Notably, symptomatic AHPs predominantly affect women, who account for approximately 90% of cases[88]. Some patients experience exacerbations linked to the menstrual cycle, as estrogen and progesterone can induce cytochrome P450 enzymes, such as CYP3A4, thereby exacerbating symptoms of AIP[37]. Multiple factors, including fasting, infections, certain porphyrinogenic drugs, physical exertion, and psychological stress, may trigger acute attacks of AIP. These factors promote hepatic cytochrome P450 gene expression, potentially initiating or aggravating the disease[6,96]. The hallmark of AHPs is unexplained severe abdominal pain, often accompanied by gastrointestinal symptoms such as nausea, vomiting, and constipation[88]. The pain is diffuse and variable in duration, and may radiate to the chest, back, or limbs[18]. Neurological involvement is multifaceted, affecting the peripheral, autonomic, and central nervous systems. Autonomic dysfunction may present as tachycardia, hypertension, and agitation, while psychiatric manifestations, such as anxiety, depression, and neuroasthenia, are common, with insomnia often being an early symptom[18]. Peripheral neuropathy may lead to lower limb weakness or flaccid paralysis. In contrast, central nervous system involvement can cause hyponatremia and water intoxication, possibly due to the syndrome of inappropriate antidiuretic hormone secretion[97].

Hepatic complications of AHPs

While overt hepatic dysfunction is uncommon in AHPs, some studies have reported mild-to-moderate elevations in serum aminotransferase levels[98,99]. The underlying mechanism remains unclear but may be associated with iron overload or coexisting conditions, such as metabolic-associated fatty liver disease. Liver biopsy may be warranted for further evaluation. Notably, AIP is recognized as an independent risk factor for HCC, regardless of symptomatic attacks[95]. A study from Sweden involving 62 patients with AIP identified 22 cases of HCC, despite the absence of HCV infection, alcohol abuse, or significant cirrhosis[100]. Furthermore, a cross-sectional study conducted by the American Porphyrias Consortium estimated an HCC prevalence of 1.5% among patients with AHP[101]. Unlike in other chronic liver diseases, HCC in patients with AHP can develop in the absence of cirrhosis. Interestingly, the incidence of HCC in AHPs is twice as high in women as in men, which contrasts with the general population, where HCC is more prevalent in men[102]. These findings underscore AHP as an independent risk factor for HCC[103]. However, even asymptomatic carriers of HMBS mutations appear to be at an elevated risk for HCC[104]. Given these findings, routine liver imaging surveillance is recommended for all patients with AHP, regardless of clinical symptoms, starting at age 50 years[105].

Renal complications of AHPs

Chronic kidney disease (CKD) is a well-recognized complication of AHPs. Data from the Porphyria Consortium indicate that 29% of patients with AHP develop CKD[106], with studies suggesting that approximately 45% of patients with AHP are affected[107]. Moreover, AIP is an independent risk factor for CKD[107]. AHP-related CKD (PAKD) progresses insidiously, with an average annual decline in estimated glomerular filtration rate (eGFR) of approximately 1 mL/minute/1.73 m². Hypertension is commonly observed in patients with AIP; however, the association between AIP and CKD appears independent of hypertensive status[107]. Renal biopsy findings typically reveal tubular atrophy, thickening of the basement membrane, and interstitial fibrosis, resulting in chronic tubulointerstitial nephropathy. In addition, some cases exhibit focal cortical atrophy associated with chronic fibrous intimal thickening[107].

Current therapies

Prevention strategies: AHPs are characterized by a marked upregulation of hepatic ALAS1, leading to increased production and accumulation of ALA and PBG. As ALAS1 plays a central role in disease pathogenesis, it represents a key therapeutic target in AHPs[89,90]. The cornerstone of AHP management is the avoidance of triggers that induce ALAS1 expression. Patients are advised to maintain a well-balanced carbohydrate intake while avoiding fasting or low-carbohydrate diets, as these may exacerbate disease activity[18]. Additional precipitating factors, including alcohol consumption, smoking, infections, and certain medications, should also be minimized. Drugs with a high potential for inducing acute attacks include barbiturates, diazepam, diclofenac, carbamazepine, nifedipine, and sulfasalazine, among others[18]. To assist in medication selection, the American Porphyria Foundation (https://porphyriafoundation.org/drugdatabase/) and the European Porphyria Network (http://www.drugs-porphyria.org/) provide evidence-based drug safety guidelines for both patients and clinicians. Table 2 catalogs clinically prevalent red-box warning medications in porphyria, denoting agents very likely unsafe for prolonged use in acute porphyrias, and their prescription should be restricted to urgent indications with universal precautionary protocols (http://www.porphyriadrugs.com).

Table 2 Categorization of high-risk pharmacological agents in porphyria.

Drug category	Drug name
Psychiatric drugs	Phenobarbital, Phenytoin, Chlorzoxazone, Diphenhydramine, Carbamazepine, Sodium Valproate, Oxcarbazepine, Ergometrine, Methyldopa, Flurazepam
Intravenous anesthetics	Thiopental sodium
Antimicrobial drugs	Voriconazole, Itraconazole, Fluconazole, Trimethoprim, Chloramphenicol, Erythromycin, Sulfasalazine, Sulfamethoxazole, Rifampicin, Rifapentine, Ritonavir, Nevirapine, Dapsone, Furantoin
Hormonal drugs	Nandrolone, Estrogen drugs, Oral contraceptives, Mifepristone, Danazol
Other drugs	Spironolactone, Praziquantel, Hydralazine

All listed medications are prescribed only for urgent indications. Clinical precautions must be strictly followed in all patients due to potential risks. Consult prescribing guidelines before administration.

Therapeutic strategies: Since disease pathogenesis is driven by ALAS1 upregulation, therapeutic interventions have focused on its suppression. Conventional treatments include carbohydrate loading, intravenous glucose administration, heme infusion, and, to a lesser extent, cimetidine therapy. More recently, RNA interference (RNAi) therapy has emerged as a targeted approach, and in refractory cases, liver transplantation remains a definitive intervention.

Oral or intravenous glucose (300-500 g/day) suppresses hepatic ALAS1 expression and reduces porphyrin precursor levels, thereby alleviating symptoms in patients with AIP. However, glucose therapy has limited efficacy and is typically beneficial only in mild acute attacks[108]. In contrast, intravenous heme infusion is a more potent method for suppressing hepatic ALAS1. Heme replenishes the hepatic heme pool, downregulates ALAS1, and reduces the production of porphyrin precursors, thereby improving clinical symptoms[109]. In life-threatening acute AIP attacks, early administration of heme is recommended to improve patient outcomes. Early administration of hemin is critical in life-threatening acute attacks, with a standard regimen of 3-4 mg/kg per day for four consecutive days. In patients with frequent relapses, prophylactic heme infusions may be administered weekly or biweekly[110]. However, despite its efficacy, repeated hemin administration is associated with potential long-term complications. Chronic exposure may induce tolerance through the activation of heme oxygenase-1, the rate-limiting enzyme in heme degradation, leading to depletion of hepatic heme stores and recurrent attacks with a diminishing therapeutic response[109]. Additionally, heme therapy has been linked to thromboembolic events, iron overload, and, in some cases, hepatic fibrosis or cirrhosis[111,112]. Furthermore, cimetidine has been shown to inhibit ALAS1 and is sometimes used for acute attacks of AHPs[113]; however, there is insufficient evidence to support its efficacy, and no compelling rationale exists for its use at any stage of acute porphyria. In female patients, hormonal fluctuations, particularly those associated with the menstrual cycle, are significant triggers for AHP attacks. For patients with menstruation-associated recurrent attacks, GnRH agonists have been used to suppress ovulation, thereby reducing attack frequency and severity; however, the long-term efficacy of this approach remains a subject of debate[114].

Givosiran, a small interfering RNA (siRNA) targeting ALAS1, has demonstrated efficacy in reducing the frequency of acute attacks and alleviating symptoms such as severe abdominal pain. In a phase III clinical trial, givosiran significantly decreased the annual attack rate and improved patient-reported outcomes. Based on these findings, the United States Food and Drug Administration (FDA) approved givosiran in November 2019 for the treatment of AHP, with a recommended dose of 2.5 mg/kg administered subcutaneously once a month[99,115]. While givosiran represents a major therapeutic advancement, its use is associated with an increased risk of adverse events, including renal and hepatic dysfunction. Regular monitoring of renal function, liver enzymes, and hypersensitivity reactions is recommended. Furthermore, the high cost of therapy remains a barrier to widespread clinical adoption.

Liver transplantation remains the ultimate therapeutic option for patients with recurrent, treatment-refractory AHP. By eliminating hepatic ALAS1 overactivity, transplantation offers the potential for complete disease resolution. However, its application is limited by organ availability, high costs, and the risks associated with lifelong immunosuppression.

CONCLUSION

Porphyrias represent a group of rare inherited metabolic disorders characterized by defects in heme biosynthesis, leading to the pathological accumulation of porphyrins and their precursors. These compounds exert direct hepatotoxic effects, resulting in liver injury, cholestasis, and an elevated risk of HCC. Diagnosis remains challenging due to nonspecific symptoms, biochemical heterogeneity, and overlapping features with common hepatobiliary disorders. Current limitations include the lack of sensitive and specific biomarkers, the incomplete adoption of genetic testing in clinical practice, and the ambiguous interpretation of certain genetic variants. To address these gaps, the development of noninvasive diagnostic tools, such as metabolomic profiling of blood/urine or exosome-based biomarkers, is critical. While the fundamental pathophysiology of porphyrias is increasingly understood, key mechanistic questions persist. The molecular drivers of porphyrin-induced liver injury, including protein aggregation, oxidative stress, and subtype-specific vulnerabilities, require further elucidation. Notably, the carcinogenic mechanisms underlying porphyria-associated HCC remain poorly defined, with unresolved roles of iron overload, chronic inflammation, and genotoxic porphyrin derivatives. Future studies should prioritize advanced models, such as humanized liver murine systems, to recapitulate the dynamic accumulation of porphyrins and the associated injury cascades, alongside proteomic investigations to map porphyrin–protein interactions and identify hepatotoxic targets.

Current therapeutic strategies focus on symptom management and porphyrin reduction but fail to address enzymatic defects. Conventional approaches (e.g., phlebotomy, heme infusions) are palliative and burdened by long-term complications, including iron overload and thromboembolic risks. Liver transplantation, while life-saving in end-stage disease, carries recurrence risks in protoporphyria, necessitating novel strategies to prevent post-transplant relapse.

Recent advances in precision medicine hold transformative potential for managing porphyria. CRISPR/Cas9-mediated allele-specific gene correction has demonstrated scarless repair of UROS mutations in CEP induced pluripotent stem cells. At the same time, hepatocyte-targeted AAV8 vectors restored HMBS activity in AIP mice, preventing toxin accumulation for > 36 weeks[116,117]. RNAi platforms, exemplified by the FDA-approved ALAS1-targeting siRNA givosiran, reduce urinary porphyrin precursors by > 90% and acute attack frequency in clinical trials (NCT04056481, NCT02949830, NCT02452372). Expanding these approaches—including mRNA-based enzyme replacement and multi-target RNAi—holds promise for broader porphyria subtypes[118-121]. However, clinical translation requires rigorous validation of long-term safety (e.g., AAV immunogenicity, CRISPR off-target effects) and efficacy in diverse genetic backgrounds[122]. Multidisciplinary care remains the cornerstone of management. Tailored surveillance protocols for HCC and renal complications, patient education on trigger avoidance, and standardized guidelines for hematopoietic stem cell transplantation are urgently needed. By integrating mechanistic insights, innovative therapies, and collaborative care models, we can mitigate the lifelong burden of porphyria-associated liver disease and improve outcomes across this complex spectrum.