Noncirrhotic portal hypertension misdiagnosed as liver cirrhosis: A rare case

Portal hypertension (PH) is defined by a pathological increase in the pressure of the portal venous system,1 with liver cirrhosis as the most common cause. However, some other noncirrhotic diseases might cause PH; a condition referred to as noncirrhotic PH (NCPH).2 NCPH is a rare disease characterized by clinical signs of PH in the absence of cirrhosis, presenting with complications of PH including ascites, splenomegaly, esophagogastric varices, and variceal bleeding.3 Because of the similarities in clinical manifestations and imaging signs, NCPH is easily misdiagnosed as liver cirrhosis and thus raises difficulties in differential diagnosis. Although liver biopsy is still the gold standard for diagnosis,4 extensive workup including laboratory testing, hepatic imaging and liver biopsy is recommended for comprehensive NCPH diagnosis. Here we report a rare case of NCPH that was misdiagnosed as liver cirrhosis through a multidisciplinary approach including imaging, liver pathology and whole exome sequencing (WES). A 43-year-old female patient presented with fatigue, abdominal distension, increased abdominal circumference, and mild edema of the lower limbs for nearly 1 year. She had a 20-year history of alcohol consumption (250 g/d) and 3 month for Gynura segetum intake, a Chinese herbal medicine with the potential to cause liver damage. She had no history of liver, genetic, or tumor disease. A plain computed tomography (CT) scan was performed at a local hospital and showed ascites and splenomegaly, which indicated liver cirrhosis. Her physical examination showed a yellow color of the skin, mucus membranes, and eyes. Spider naevi and liver palm were also found. The abdomen was slightly distended with shifting dull pain, without rebound tenderness and muscle rigidity. The laboratory findings were as follows: routine blood tests showed low white blood cell count (3.02 × 109/L), hemoglobin (88 g/L), and platelet count (44 × 109/L). Hepatic function tests showed increased levels of aspartate transaminase (64.35 μ/L), total bilirubin (85.8 μmol/L), direct bilirubin (44.2 μmol/L), indirect bilirubin (41.6 μmol/L), total bile acid (TBA; 195.2 μ/L), alkaline phosphatase (178.05 μ/L), but low albumin (28 g/L). Coagulation test showed a prolonged clotting time (prothrombin time 19 s and prothrombin activity 45.4%). The hepatotropic viruses including hepatitis A–E and antibodies of autoimmune hepatitis were all negative. Other examinations, such as the ceruloplasmin and tumor markers, were also normal. Her abdominal contrast-enhanced CT showed liver shrinkage, mild ascites, splenomegaly, esophagogastric varices, and significantly enlarged portal vein (PV, diameter of 17 mm), which indicated presence of liver cirrhosis and PH. Contrast-enhanced magnetic resonance imaging showed normal hepatic vein and inferior vena cava without obstruction, but dilated PV. Additionally, gastroscopy showed esophageal vein exposure and portal hypertensive gastropathy. To clarify the etiology, liver biopsy was performed and the pathological features were as follows: hematoxylin and eosin staining showed structural disorders of hepatic lobules, irregular arrangement of liver plates, massive hepatocyte swelling, and ballooning with neutrophil-rich parenchymal inflammation around the periportal region (Figure 1A), which indicated moderate liver injury and chronic hepatitis. Multiple sinusoidal dilatation was observed (Figure 1B) and no vascular endothelial damage was observed. The PV was enlarged and many small abnormal vessels were evident, classified as periportal angiogenesis (arrow) (Figure 1C). The enlarged PV herniated into the adjacent parenchyma, known as herniated PV (arrow) (Figure 1D). Masson and reticulin staining showed moderate perisinusoidal fibrosis without hyperplasia of fiber interval and regenerative nodules (Stage 2 fibrosis) (Figure 1E,F), indicating no formation of liver cirrhosis. Cytokeratin 7 staining showed massive cholestasis in hepatocytes and cytokeratin 19 staining showed hyperplasia of the small bile duct (Figure 1G,H). The above characteristics of liver pathology indicated marked hepatocyte injury and PH without cirrhosis. Additionally, WES of blood samples was performed to exclude inherited metabolic disorders. Mutations were finally detected for four genes, ATP8B1, NPC1, UGT1A1, and PKHD1, which were associated with metabolic dysregulation of lipids, bile acid, and cholesterol, as well as drug metabolism disorder. In short, combined with the medical history, clinical symptoms, laboratory tests, imaging, liver pathology, and WES result, the patient was finally diagnosed with NCPH, drug-induced liver injury (DILI), and alcoholic liver fibrosis. Liver cirrhosis accounts for nearly 90% of cases of PH, whereas 10% of PH occurs in diseases without cirrhosis.5 NCPH is a heterogeneous group of liver disorders of vascular origin leading to PH in the absence of cirrhosis. Many etiologies exist that can cause NCPH, such as schistosomiasis, heart failure, Budd–Chiari syndrome, and hepatic vascular diseases.6 The etiology of NCPH is classified into three categories based on the anatomical site of blood flow resistance as follows:3 (1) prehepatic: including extrahepatic PV obstruction, and splenic vein thrombosis; (2) intrahepatic (subdivided into presinusoidal, sinusoidal, and postsinusoidal): including noncirrhotic portal fibrosis, idiopathic portal hypertension, and idiopathic NCPH, which result from chronic liver diseases (chronic viral hepatitis, nonalcoholic or alcoholic steatohepatitis, and autoimmune hepatitis) and diseases causing PH (congenital liver fibrosis, sarcoidosis,and schistosomiasis); (3) posthepatic: obstruction of the hepatic veins or inferior vena cava including Budd–Chiari syndrome, right heart failure, and constrictive pericarditis. Regardless of the etiology and cause, patients always present with signs or symptoms of PH, which could be easily misdiagnosed as liver cirrhosis. The patient in this case had a long history of heavy alcohol consumption, which suggested chronic liver injury and inflammation, which gradually developed to liver fibrosis. Alcohol-induced fibrosis, as an intrahepatic cause, might induce PV blood flow obstruction, which led to PH in the present case. To exclude inherited metabolic diseases of the liver, WES was used, which revealed four gene mutations, namely ATP8B1, NPC1, UGT1A1, and PKHD1, which were associated with disorders of lipid, bile acid, cholesterol, and drug metabolism, respectively. These metabolic disorders matched with her clinical phenotype, as alcohol drinking, herbal medicine intaking, jaundice, and cholestasis. WES validated the pathophysiology and pathogenesis of chronic liver injury in this patient. Hence, diagnosis of NCPH could be based on a comprehensively extensive work-up including imaging, liver biopsy, and WES, which need more evidence to validate. Typically, in NCPH, liver function is preserved and liver failure with ascites or encephalopathy is rare, even when the signs of PH are clinically evident.7 However, the patient in this case presented with moderate liver injury characterized by elevated transaminases, bilirubin, and TBA levels, accompanied by symptoms of liver damage such as fatigue, anorexia, and jaundice. The liver injury was further confirmed by liver histopathology, which showed hepatocyte swelling, ballooning degeneration, infiltration of inflammatory cells, intrahepatic cholestasis, and hepatocyte regeneration. Her liver damage might be associated with long exposure to G. segetum, a Chinese herbal medicine containing pyrrolizidine alkaloids that can severely damage the liver.8, 9 DILI can symptomatically mimic both acute and chronic liver diseases.10, 11 We hypothesize that long-term use of herbal medicine elicited hepatocyte damage based on alcoholic-induced fibrosis; however, sinusoidal fibrosis related to the drug usage cannot be excluded, which needs verification. In conclusion, NCPH is easily misdiagnosed as liver cirrhosis because of the similarities in clinical presentation and imaging signs, thus raising difficulties in their diagnosis. A comprehensive understanding of the etiology, clinical manifestations, imaging, and liver biopsy are needed for differential diagnosis. Additional diagnostic tools are required to validate these finding in the future. Lingling Yang wrote the manuscript and Zhen Zhou collected the data. Liming Xiao, Lifang Chen, Wugen Li, and Yingqun Xiao were responsible for data analysis. Zhili Wen supervised the study. All authors have read and approved the final version to be published. This study was supported by the National Natural Science Foundation of China (grant number 82103655). The authors declare no conflict of interest. Ethical approval for this study was waived by Ethical Committee of The Second Affiliated Hospital of Nanchang University. The Patient was invited to participate and written informed consent was obtained. All relevant data are within the paper.