Porphyrias are a group of hereditary metabolic disorders caused by defects in enzymes involved in the heme biosynthesis pathway. EPP is an autosomal recessive disorder resulting from the loss of ferrochelatase activity, which disrupts heme biosynthesis and leads to the accumulation of protoporphyrin in various tissues, including the skin, blood, and liver (1). This accumulation causes the characteristic clinical manifestations of the disease. EPP is classified as a rare condition, with incidence rates reported in international studies ranging from 2 to 5 cases per 1,000,000 individuals (2). Clinically, EPP mainly manifests as increased skin sensitivity, with a small portion affecting the liver. Macroscopic examination of the liver in EPP patients typically reveals a dark appearance, while microscopic analysis shows cholestatic changes and birefringent deposits, which form a characteristic Maltese cross pattern under polarized light microscopy. This report describes a case of an EPP patient admitted for abnormal liver function, who was diagnosed after a detailed medical history review, liver biopsy, and whole-exome sequencing. Additionally, a novel mutation, c.804 + 1del, was identified in the FECH gene, which may be associated with the disease.

EPP is an autosomal recessive genetic disorder caused by a deficiency of ferrochelatase activity in the heme biosynthesis pathway, leading to the accumulation of protoporphyrin in tissues such as the skin, blood, and liver, thereby triggering associated clinical symptoms. The clinical presentation of EPP is primarily characterized by heightened skin sensitivity, with a minority of patients developing liver damage. The liver of EPP patients appears dark upon macroscopic examination, and under microscopy, dense brown-red protoporphyrin polymer crystals can be observed within the bile canaliculi, hepatocytes, and Kupffer cells. These crystals exhibit birefringence under polarized light microscopy, showing a “starry sky” appearance, with some displaying the characteristic Maltese cross pattern (1). Additionally, varying degrees of hepatocyte degeneration and necrosis are observed, with more severe cases showing different levels of fibrosis and cirrhosis.

The patient in this case was admitted multiple times, presenting with abdominal pain and scleral jaundice. Laboratory tests indicated abnormal liver function and partial positivity for autoimmune hepatitis antibodies. Autoimmune hepatitis was initially considered clinically, and a liver biopsy was sent to the pathology department. Hematoxylin and eosin (HE) staining revealed destruction of the hepatic lobular architecture, proliferation of fibrous tissue in the portal areas, with lobular division leading to the formation of hepatocyte clusters. Cholestatic changes are observed in both hepatocytes and hepatic sinusoids. After repeated careful slide examination by the pathologist, immunohistochemistry and special staining were performed. The results showed positive Masson’s trichrome staining, with small bile ducts expressing CK7 and CK19, consistent with cirrhosis. CD138, CD4, CD8, IgG, IgG4, and IgM were negative, ruling out autoimmune hepatitis. Special staining results showed negative staining for iron, copper, and glycogen, further excluding hemochromatosis (12), Wilson’s disease (13), and glycogen storage diseases (14). At this point, the cause of the patient’s condition remained unclear. Microscopic examination revealed morphological abnormalities in bile plugs within hepatocytes and liver sinusoids. These brownish substances, resembling bile plugs, had a deeper color and denser structure, whereas typical bile plugs appear homogeneous, lightly stained, and lack granular material. The tissue biopsy report notes the presence of an abnormal black coloration in the liver specimen. Considering the patient’s relatively young age, the pathologist suspected porphyria. After repeated history taking, the patient informed the clinical team of a family history of “skin photosensitivity,” suggesting the possibility of porphyria. The pathologist further observed these brownish particles under polarized light microscopy, where they showed red birefringence. Some particles exhibited the characteristic Maltese cross pattern, consistent with the pathological features of porphyria.

Given the complexity of porphyria classification, genetic testing was recommended. The results revealed abnormalities in the FECH gene, with two heterozygous variants: c.804 + 1del and c.315-48 T > C. EPP is primarily caused by FECH gene mutations. In this case, the patient has autosomal recessive inheritance, and the clinical features of the disease caused by these mutations align with the patient’s symptoms, including the family history of “skin photosensitivity,” abdominal pain, and scleral jaundice. Notably, whole-exome sequencing also revealed a canonical splice-site mutation in the FECH gene (NM_000140.5: c.804 + 1G > C). This variant involves a substitution of guanine (G) to cytosine (C) at the +1 position of intron 804 of the FECH gene, which is a highly conserved core nucleotide of the donor splice site. Consequently, this change is expected to disrupt normal RNA splicing, leading to a loss of function (LOF) via aberrant transcript processing. This variant has not been reported in the gnomAD population database. In accordance with the guidelines established by the American College of Medical Genetics and Genomics (ACMG) and the Clinical Genome Resource (ClinGen), this variant is classified as pathogenic and is predicted to adversely affect the structure and function of the FECH protein. Additionally, the patient was found to have mutations in the UGT1A1 gene, including a heterozygous single nucleotide substitution variant in the upstream regulatory region (c.-3275 T > G) and a heterozygous missense mutation in the coding region (c.211G > A:p. G71R). The UGT1A1 gene mutation leads to autosomal recessive Gilbert syndrome. Gilbert syndrome, also known as congenital non-hemolytic jaundice or hereditary unconjugated hyperbilirubinemia, is a disorder of bilirubin metabolism that typically presents with subtle onset and usually without obvious symptoms. The clinical hallmark is elevated unconjugated bilirubin. The disease does not damage hepatocytes or bile duct cells, so liver enzymes (ALT, AST) and biliary enzymes (ALP, γ-GGT) are typically normal. In this case, the patient’s direct bilirubin (118 μmol/L) and total bilirubin (221.1 μmol/L) were both elevated, suggesting an increase in indirect bilirubin, which is consistent with the clinical features of Gilbert’s syndrome. However, the patient also had elevated liver enzymes (ALT 412 U/L, AST 201 U/L), which cannot be excluded as a result of EPP with concomitant cirrhosis. Due to financial constraints, the patient did not undergo family genetic pedigree testing.

In summary, the clinical presentation of this patient was atypical, with no obvious skin lesions. Due to limitations in testing conditions, quantitative measurements of blood, urine, and fecal protoporphyrin were not performed, which significantly complicated the diagnosis. Ultimately, through close collaboration between the pathologist and the clinical team, EPP was diagnosed, confirmed by genetic testing. EPP is a rare genetic metabolic disorder that is prone to misdiagnosis, necessitating pathologists to have extensive diagnostic experience. In routine pathological diagnosis, when dense brown particles are observed within liver sinusoids or hepatocytes, in addition to considering bile plug formation, other metabolic liver diseases, such as Wilson’s disease, glycogen storage diseases, and hemochromatosis, should also be considered, which can be differentiated through special staining. Diagnosing EPP requires pathologists to make a comprehensive diagnosis based on the patient’s history, clinical presentation, and laboratory test results. When EPP is suspected, polarized light microscopy should be employed to observe whether the characteristic pathological features are present. Early genetic testing should be conducted, and active treatment should be initiated promptly after diagnosis to improve the patient’s prognosis.