CASE REPORT
A 16-year-old adolescent boy presented to us with a history of progressive jaundice and recurrent attacks of acute abdominal pain for the past 5 months.1 Abdominal pain was episodic, with 1 or 2 episodes per month lasting for 7 to 10 days. It was diffuse and severe, requiring hospital admissions and intravenous analgesics. He also had a history of photosensitivity since the age of 5 years. There was no history of fever, blisters, oral ulcers, musculoskeletal symptoms, or history suggestive of neuropsychiatric manifestations. On examination, he had icterus; atrophic scarring; and hyperpigmentation of face, hands, and feet (Figure 1) along with nontender hepatosplenomegaly.
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Figure 1.: Atrophic scarring and pigmentation of the face (A and B), hands (C), and feet (D).
Complete hemogram revealed anemia (hemoglobin: 9.9 g/dL, normal range: 12–26 g/dL) with normal total leukocyte (9 × 109/L, normal range: 4 to 11 × 109/L) and platelet (174 × 109/L, normal range: 150 to 450 × 109/L) counts. He had hyperbilirubinemia (total bilirubin: 8.65 mg/dL, normal range: 0–1.0 mg/dL, direct bilirubin: 4.3 mg/dL, normal range: 0–0.3 mg/dL) with elevated liver enzymes (aspartate aminotransferase: 462 IU/L, normal range: 15–40 IU/L, alanine aminotransferase: 256 IU/L, normal range: 15–40 IU/L, alkaline phosphatase: 262 IU/L, normal range: <128 IU/L, and normal prothrombin time [international normalized ratio: 1.2, normal range <1.2]). Extensive etiological workup for usual causes of liver disease including viral markers (hepatitis B surface antigen, anti-hepatitis C and immunoglobulin M antibodies against hepatitis A, hepatitis E, cytomegalovirus, Epstein-Barr and herpes simplex virus), autoimmune markers (antinuclear antibody, anti-smooth muscle antibody, anti-liver kidney microsome type 1 and anti-soluble liver antigen antibody), serum ceruloplasmin, and immunoglobulin A tissue transglutaminase were unrevealing. Given the history of photosensitivity, a possibility of systemic lupus erythematosus and porphyrias was considered. However, anti-double stranded DNA, anti-Smith antibody, and urinary porphobilinogen were absent. Esophagogastroduodenoscopy revealed small, low-risk esophageal varices. A triple-phase abdominal computed tomography scan corroborated the clinical examination findings of hepatosplenomegaly, but there was no other imaging evidence of portal hypertension (Figure 2). Magnetic resonance cholangiopancreatography of the abdomen did not reveal any biliary abnormalities.
Figure 2.: Abdominal computed tomography showing hepatosplenomegaly.
Liver biopsy showed distorted lobular architecture with porto-portal and porto-central bridging fibrosis. The interlobular bile ducts, ductules, canaliculi, and hepatocytes showed deposition of dark brown pigment in the form of large blobs and droplets. The deposits were negative for Perls stain but strongly positive for Schmorl stain (peacock blue). This pigment showed birefringence with a Maltese-cross pattern under polarizing microscopy. Electron microscopy revealed medusa-head appearance consistent with protoporphyrin deposition (Figure 3). On genetic testing, compound heterozygous variants of the ferrochelatase (FECH) gene including c.481+1G>A (splice-site variant) at intron 4 and c.333-48T>C at intron 3 were identified, which confirmed the diagnosis of erythropoietic protoporphyria (EPP).
Figure 3.: Microphotographs showing (A) distortion of lobular architecture as depicted by the Masson trichrome (left) (100×) and reticulin stains (right) (40×); (B) deposition of brownish pigment within the ductules, canaliculi, and hepatocytes (hematoxylin and eosin, 400×); (C) pigment negative for Perls stain (400×); (D) pigment positive for Schmorl stain (400×); (E) Maltese-cross birefringence under polarizing microscopy (100×); and (F) a Medusa-head type of electron dense structure in ultrastructure (scale bar added).
He was managed with a combination of ursodeoxycholic acid, vitamin E supplementation, cholestyramine, and plasma exchange with partial improvement in symptoms and liver function tests. The patient and his parents have been counseled about the need for liver transplant and bone marrow transplant, and they are considering the same.
DISCUSSION
First described in 1961, EPP typically presents with cutaneous manifestations as painful, nonblistering photosensitivity, which may progress to lichenification, pigmentation, and later scarring after repeated exposures.2,3 The absence of blisters helps to clinically differentiate EPP from other cutaneous porphyrias such as porphyria cutanea tarda. Nevertheless, delay in diagnosis is common. In one series, the median delay between symptom onset and diagnosis was 13 years, with one-fifth of the patients having seen more than 10 physicians before the diagnosis.3 Our patient also had a history of photosensitivity for past 11 years and had sought multiple consultations in various tertiary and academic hospitals before EPP was finally diagnosed. Delayed diagnosis in EPP is attributable to the condition's rarity and plethora of clinical differentials for photosensitivity; transient nature of cutaneous manifestations in the early disease course; and porphyria screening using urinary porphyrin levels, which are normal in EPP. Screening for EPP involves demonstration of elevated total erythrocyte protoporphyrin, which on fractionation predominantly comprises metal-free protoporphyrin (>85%). However, the hematofluorometers used in many laboratories measure zinc-protoporphyrin because they were originally designed to detect lead poisoning and facilities for measuring metal-free erythrocyte protoporphyrin are not widely available.4 Because we did not have access to testing for metal-free erythrocyte protoporphyrin levels and were strongly suspecting protoporphyria based on clinical and liver biopsy findings, we directly proceeded to genetic tests to establish the diagnosis of EPP.
Previously, EPP was considered to be an autosomal dominant condition with incomplete penetrance. It is now known that EPP is usually inherited in an autosomal recessive pattern and involves compound heterozygosity of a severe FECH variant (deletion, missense, nonsense, splice-site variants resulting in complete loss or drastic reduction in functional enzyme) together with another FECH variant associated with slightly decreased expression of FECH (hypomorphic variant).5 Our patient was compound heterozygous for FECH variants with a 5′splice-site variant (c.481+1G>A) and hypomorphic variant (c.333-48T>C). The hypomorphic variant c.333-48T>C directs use of aberrant splice sites and is associated with a relatively less stable mRNA that is susceptible to degradation with a consequential decrease in FECH levels. However, the homozygous presence of the c.333-48T>C variant is not associated with clinical manifestations and as such this variant is present in 10% of healthy Whites and may be even more common among oriental Asians.6–8 This is the first report of these FECH variants in an Indian patient.
Hepatobiliary involvement in EPP is a consequence of protoporphyrin accumulation in the liver causing cholestatic and oxidative damage. Splenomegaly results in sequestration and destruction of RBCs, which stimulates erythropoiesis, resulting in an increased production of protoporphyrin and deposition in the liver, thereby setting up a vicious cycle. Protoporphyrin in the liver appear as dark brown deposits that show birefringence with a Maltese-cross appearance on polarizing microscopy. Hepatic involvement occurs in approximately 5% patients, although higher involvement (up to 20%) has been reported in some series.1,9–11 Factors predisposing a proportion of patients with EPP to develop liver disease is poorly understood. Analysis of 112 patients with EPP from 93 families revealed that patients with null variants that produce a truncated protein have a significantly higher risk of liver disease than those with missense variants that produce a functionally impaired enzyme with intact length.12 Our patient too had a null variant in the form of splice-site mutation c.481+1G>A, which may have predisposed him to develop liver disease. In conclusion, although rare, EPP is an important cause of nonblistering, cutaneous photosensitivity that may lead to hepatic involvement. Awareness and appropriate diagnostic work-up is required to avoid delays in diagnosis, which can severely impair quality of life in these patients.
Various treatment strategies have been tried in EPP with liver involvement, although the evidence is limited. These include ursodeoxycholic acid (increases protoporphyrin excretion into bile), hematin and red blood cell transfusion (to reduce protoporphyrin production), cholestyramine or activated charcoal (to interrupt enterohepatic circulation of protoporphyrins), hemodialysis or plasmapheresis (to remove circulating protoporphyrins), and vitamin E (antioxidant and possible cytoprotective effect).1,7 Liver transplant is not a definitive cure because there is a high chance of recurrence because of continued production of protoporphyrin in the bone marrow.13 Hence, liver transplant followed by bone marrow transplant should be considered when indicated and feasible.1
DISCLOSURES
Author contributions: N. Bhagat and P. Singh: patient evaluation and management and writing the initial draft. A. De: patient evaluation and management and critical revision. S. Mitra: histopathological analysis, electron microscopy, and critical revision. A. Kumar, V. Dhanasekaran, and MV Parkhi: histopathological analysis and electron microscopy. A. Duseja: critical revision and is the article guarantor.
Financial disclosure: None to report.
Informed consent was obtained for this case report.
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