key: cord-0916123-6j1pw3yu
authors: Tafreshi, Shima; Whiteside, Ian; Levine, Irving; D'Agostino, Catherine
title: A case of secondary sclerosing cholangitis due to COVID-19
date: 2021-07-27
journal: Clin Imaging
DOI: 10.1016/j.clinimag.2021.07.017
sha: 812902b198b8add88a1cfac903e4b60906bcadbe
doc_id: 916123
cord_uid: 6j1pw3yu

COVID-19 was first recognized by the World Health Organization (WHO) in December 2019 and declared a global pandemic in March 2020. Although COVID-19 primarily results in pulmonary symptoms, it is becoming apparent that it can lead to multisystemic manifestations. Liver damage with elevated AST and ALT is seen in patients with COVID-19. Although the etiology of liver damage is still debated, biliary damage is rarely seen. This case demonstrates a potential complication of COVID-19 in a previously healthy patient. The patient contracted COVID-19 in March 2020 and endured a complicated course including intubation, multiple readmissions, and chronic abdominal pain. He is now awaiting a liver transplant. Our case portrays biliary damage as an additional possible complication of COVID-19 and the importance of imaging in its diagnosis.

In December 2019 a novel coronavirus, Severe Acute Respiratory Syndrome -Coronavirus 2 (SARS-CoV-2), was recognized by the World Health Organization (WHO) 1 J o u r n a l P r e -p r o o f Up to this point, different clinical manifestations of this disease, including fever, cough, sore throat, diarrhea, loss of sense of taste or smell have been reported 2 . 80% of patients have a mild form of the disease while 5% become critically ill 2 . Liver damage is seen in 7.6-39% of patients with COVID-19, with elevation of aspartate aminotransferase (AST) greater than alanine aminotransferase (ALT), implicating the contribution of AST from sources outside the liver 5 .

There are multiple hypotheses about the cause of liver damage including direct viral damage, indirect inflammatory injury and drug related hepatotoxicity 2 . Here we report a case of secondary sclerosing cholangitis likely due to COVID-19.

Patient is a 38-year-old previously healthy male ( He returned one week later with similar symptoms. The patient underwent an ultrasound showing intrahepatic biliary ductal irregularity and a markedly thickened common bile duct ( Figure 4 ). An ERCP was then performed revealing tortuous and attenuated intrahepatic bile ducts with normal caliber extrahepatic ducts ( Figure 5 ). The patient then began evaluation for liver transplantation.

COVID-19 is a global pandemic that has spread to many countries beginning early December 2019. Three phases of COVID-19 infection have been described. The initial phase causes mild symptoms that could be mistaken for the common cold or flu. The second phase is the pulmonary phase when respiratory symptoms such as cough, shortness of breath and pneumonia are predominant. Also, hypercoagulability with blood clotting can be seen in Phase 2. The third phase, the hyperinflammatory phase, is when the body damages its own tissues due to the dysregulation of immune responses [5] [6] [7] . This maladaptive immune response can result in extensive multi-organ injury 5-8 . The respiratory system is most frequently affected but complications from the SARS-CoV-2 virus can be seen in almost every other organ system 9 . The liver is the second most common organ to be damaged by COVID-19 10 . This is more common in men and increases with older age.

The exact cause of organ injury is not completely understood and is likely multifactorial. Mild For SARS-CoV-2 to enter a target call and replicate, it needs to bind to the Angiotensin converting enzyme 2 (ACE2) receptor. It is thought that viral particles in the bowel lumen may reach the liver via the portal venous system but this deserves further investigation 2 . As there is low expression of angiotensin-converting enzyme 2 (ACE2) receptors in hepatocytes, it is thought that damage to liver cells is mainly secondary to immune-related injury from cytokine release. Additionally, in more severe disease, microthrombosis/altered coagulation, hypoxia, sepsis-related abnormalities, damage to adjacent cholangiocytes and drug hepatotoxicity (antiviral drugs and antibiotics) play a role in hepatic injury 12 . Patients with underlying liver disease are also at risk for COVID-19 and its complications, including liver injury, as well as progression of their pre-existing liver disorder 4 . This includes hepatic steatosis which is an independent risk factor for the more severe form of COVID-19 infection 13 .

During the third phase of COVID-19, cytokine release directly contributes to the extrapulmonary manifestations as stated above 9 . Additionally, cells with increased ACE2 receptor expression are vulnerable to direct viral damage 14 . This includes the cholangiocyte, the cell that lines the biliary tree. The cholangiocyte's primary function is to modify hepatocyte derived bile acid. The tight junction formed between adjacent cholangiocytes is essential for bile acid collection and excretion. SARS-CoV-2 can bind to the ACE2 cell receptor directly on the cholangiocyte, as a result disrupting this barrier and bile acid transportation through gene dysregulation. This injury causes bile acid accumulation (cholestasis) and consequent liver damage, which is severe and prolonged 15, 16 .

Our patient was previously healthy prior to contracting COVID-19. This is documented with CT imaging performed in 2010 for renal colic. At that time, the liver was normal in size and appearance without biliary pathology (Figure 1) . Early in the course of his COVID-19 infection, our patient had mild hepatocellular injury resulting in elevated LFTs. This was diagnosed clinically as hepatitis and resolved rapidly. Heterogeneous liver parenchyma and periportal edema may be seen on imaging as signs of hepatitis. During our patient's initial markedly prolonged hospitalization which was complicated by lung, heart, kidney and brain manifestations of COVID-19, he developed severe and persistent cholestasis with jaundice. The alkaline phosphatase and total bilirubin showed marked elevation. The patient's liver disease changed from an initial hepatocyte injury to a later cholangiocyte injury. CT findings revealed mild J o u r n a l P r e -p r o o f biliary dilatation with ductal/periductal enhancement/edema (Figure 2 ). MRCP showed irregular intrahepatic ducts with beading and attenuated segments and mild irregularity of the extrahepatic bile duct (Figure 3 ). This was followed by an ERCP which removed sludge and imaged similar findings of the intrahepatic ducts and a normal caliber extrahepatic bile duct ( Figure 5 other macrolides, has been linked to a low rate of acute, transient, and asymptomatic elevation of serum aminotransferases, seen in 1-2% of patients treated for short periods 17 . In rare situations, it is also linked to symptomatic liver injury. In patients with liver injury, pathology demonstrates bile duct loss which can result in chronic cholestatic liver failure if severe. Additionally, hydroxychloroquine was commonly used in combination with azithromycin for the treatment of COVID-19; however, hydroxychloroquine has not been shown to be a cause of significant liver enzyme abnormalities 18, 19 . Tocilizumab, which is also used in COVID-19 treatment, can infrequently cause hepatotoxicity with mild to moderate transaminase elevation. Severe druginduced liver injury is exceedingly unusual. 20, 21 .

Our patient's long hospital course in the intensive care unit (ICU) also must be addressed as a plausible cause of the pathologic diagnosis of secondary sclerosing cholangitis. Mechanisms of injury are related to cholestasis of critical illness and hypoxic liver/biliary injury due to circulatory and respiratory impairment requiring ventilatory support [22] [23] [24] . This ischemic insult can lead to histopathological abnormalities including cholangiocyte injury. 

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