Treatment strategy for erythropoietic protoporphyria accompanied by severe abdominal pain and liver injury

Erythropoietic protoporphyria (EPP) is a genetic disease caused by a lack of the enzyme ferrochelatase (FECH) in the heme biosynthesis pathway due to genetic defects. FECH deficiency is caused by a deleterious FECH variant in transposition to the frequently occurring hypomorphic allele or by the presence of biallelic pathogenic variants.1 EPP could lead to abnormal production and excretion of protoporphyrin IX,2 causing clinical manifestations such as skin damage and liver injury.3-5 EPP incidence is very low, and symptoms of persistent abdominal pain and jaundice are even rarer in these patients. Consequently, EPP is often overlooked in young patients with severe abdominal pain and jaundice.6 Afamelanotide treatment mostly alleviates skin symptoms.7 Cimetidine has been reported to decrease photosensitivity in addition to decreasing the concentration of erythrocyte protoporphyrin.8, 9 When a patient manifests with severe abdominal pain and liver injury, the disease becomes more complicated. No standard treatment strategies exist for EPP that is accompanied by severe abdominal pain or liver injury. Here, we report the case of a 29-year-old male with persistent intermittent severe abdominal pain lasting more than 1 month, which was accompanied by jaundice, sweating, and an inability to perform bowel movements. After liver pathology and genetic analyses, the patient was diagnosed with EPP. The patient recovered after a combined treatment featuring blood purification, glucocorticoids, ursodeoxycholic acid, and a high-sugar diet. The details of this case are as follows. A 29-year-old male patient experienced a sense of fullness and sudden pain in the upper abdomen after a meal in March 2019. Jaundice developed with yellow skin and deepened urine color in May 2019; however, he did not pay attention to these symptoms until August 10, when upper abdominal pain occurred, indicating a progressive worsening of the symptoms. The pain soon spread to the entire abdomen. Severe abdominal pain was accompanied by sweating, back radiation pain, and an inability to perform bowel movements. The patient was then admitted to a local hospital. Total bilirubin and bile acids were decreased on September 6 after blood purification using an artificial liver support system. Liver injury caused by herbal, viral, or autoimmune liver diseases were excluded after a series of examinations at the local hospital. The positron emission tomography-computed tomography (PET-CT) revealed an increase in (18F) 2-fluoro-2-deoxy-d-glucose metabolism in the pancreas and gastric wall. After multiple disciplinary team discussions, they concluded that no obvious organic space-occupying lesions were present in the patient, and jaundice caused by tumors was excluded. However, the persistent intestinal obstruction persisted, and the jaundice gradually worsened. Severe abdominal pain could not be alleviated even with morphine; the etiology was unknown, and the patient felt miserable. The patient was transported to our emergency department on September 10, 2019. Abdominal computed tomography (CT) revealed intestinal gas accumulation, abdominal effusion, and splenomegaly. After the patient was transferred to our department on September 19, 2019, we carefully reviewed the patient's medical history. The patient had a history of photosensitivity since childhood. The patient also had a clinical record of gallstones and underwent cholecystectomy when he was 26 years old. We analyzed the conditions of the patient and found that the main manifestations were abdominal pain and liver injury. Bone marrow puncture and biopsy were performed, and no blood system-related tumors were found. Furthermore, we performed abdominal CT and hepatic and spleen ultrasonography. Abdominal CT revealed decreased intestinal gas accumulation and hepatosplenomegaly. Ultrasonography revealed hepatosplenomegaly (Supporting Information: Figure S1). Meanwhile, the levels of inflammatory biomarkers were elevated (CRP, 41 mg/L; IL-6, 152 pg/mL). The patient was diagnosed with cholestatic hepatitis. The patient complained of severe paroxysmal abdominal pain, and the numerical pain rating scale (NRS) score was 9. The pain was not relieved by antipyretic or analgesic drugs. After treatment with fentanyl paste, morphine, and other pain relief agents, the NRS score decreased, but the pain persisted. Simultaneously, we quickly performed a liver puncture and performed pathological tests. Liver pathology revealed chronic cholestatic hepatitis (G2S3-4). The presence of yellow-brown particles in the liver lesions supports porphyrinosis (Figure 1). Meanwhile, FECH18q21.31 Intron5 c.599-1G>C (heterozygous), FECH18q21.31 Intron1 c.68-23C>T (homozygous), and FECH18q21.31 Intron3 c.315-48T>C (homozygous) were identified by genetic analysis. These mutations influence the FECH protein and cause a loss of normal function. Therefore, the patient was diagnosed as having EPP. We adjusted the treatment plan to protect liver function, decrease enzyme levels, promote bile excretion, and relieve pain. The patient was prescribed 40 mg of prednisolone to be taken daily; consequently, the abdominal pain of the patient was significantly relieved, and the patient was discharged from the hospital on October 15 (Supporting Information: Figure S2). The glucocorticoid dose was reduced by 4 mg every 2 weeks until discontinuation. The patient no longer complained of any abdominal pain and the liver function was significantly improved on December 9, 2019 (Supporting Information: Figure S3). The patient visited us again in January 2021 and had developed cholestatic liver cirrhosis. However, the patient did not undergo bone marrow or liver transplantation for economic reasons. EPP is a very rare genetic disease, with a prevalence of one in 50,000–75,000 individuals.10, 11 Cases with severe abdominal pain and jaundice as the main symptoms are even rarer.12 When EPP leads to late-stage liver disease, only a liver transplant can save the patient.13-15 However, the patient will relapse if the etiology is not elucidated.6, 16 Early effective treatments for this disease are of great importance.16 The cholestasis induced by protoporphyrin leads to further accumulation of protoporphyrin, initiating a vicious cycle of worsening cholestasis and reduced protoporphyrin excretion.15, 16 Exchange transfusions can be effective for EPP-related cholestatic hepatitis because it quickly lowers protoporphyrin levels, thus providing an opportunity for the liver to recover.17 For our case, blood purification treatment was initially used to treat our patient using an artificial liver support system. Meanwhile, we found that glucocorticoids and a high-sugar diet were very useful in reducing abdominal pain. Glucocorticoids may work by reducing liver inflammation and biliary edema and accelerating bile excretion. Eliminating cholestasis also accelerates porphyrin excretion.15, 16 Combined with ursodeoxycholic acid, the patient's liver function quickly recovered. In this study, we describe the diversity and concealment of the clinical manifestations of EPP, aiming to attract more attention from clinicians to reduce both misdiagnoses and missed diagnoses. We hope to share our experiences in diagnosing and treating unexplained abdominal pain. Distinguishing between acute abdomen and EPP and being more cautious about emergency laparotomy and other operations is important. EPP, which can be easily overlooked, can be diagnosed quickly and accurately by liver pathology and genetic analysis.16, 18 The treatment strategy combining blood purification, glucocorticoids, ursodeoxycholic acid, and a high-sugar diet was effective for the remission of EPP accompanied by severe abdominal pain and jaundice. However, the optimal long-term treatment strategy for EPP and cholestatic cirrhosis caused by EPP requires further research. Xiaoxin Wu and Xiumei Zhou analyzed the data and wrote the manuscript. Shuai Zhao, Keting He, Wenxin Zhoudi, and Shangci Chen revised the manuscript. Xiaowei Xu approved the final version of the manuscript. All the authors have approved the final manuscript and its submission. The authors would like to thank the patient, Dr. Songjia Tang for assistance with English editing, and Jinyu Inspection Co. Ltd. for the help with genetic analysis. This work was supported by the Zhejiang Provincial Natural Science Foundation of China (No. LQ21H190004) and the National Natural Science Foundation of China (No.82300004). The authors declare no conflict of interest. This study was conducted in accordance with the Declaration of Helsinki (revised 2013). This study was approved by the Ethics Committee of the First Affiliated Hospital of Zhejiang University School of Medicine (Ethical approval No. 2022-861). Written informed consent was obtained from the patient for publication of any potentially identifiable images or data included in the manuscript. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.