A 43-year-old woman with a medical history of stage IIIB cutaneous melanoma previously receiving adjuvant immunotherapy with nivolumab presented to the emergency department with a 4-day history of nausea, vomiting, abdominal pain, and jaundice. Symptoms began with nausea and vomiting after eating a meal. The following morning she had dull right upper quadrant and periumbilical abdominal pain. Her nausea persisted, and she had multiple episodes of nonbloody nonbilious emesis. Later that day, she developed jaundice and had fever and chills, which prompted her presentation to the emergency department. She had been treated with nivolumab for melanoma, but this was discontinued 2 months before presentation owing to lack of insurance coverage. The patient also had a history of alcohol abuse disorder, drinking 2 to 3 vodka drinks per day. She took multiple over-the-counter vitamins and various supplements including more than 14 different vitamins and supplements such as iron, boron, picolinate, chromium, milk thistle, and turmeric, but was not taking any prescribed medications. She denied acetaminophen ingestion, or any other drugs.

In the emergency department, vital signs were stable with a temperature of 36.8°C, heart rate 80 beats/min, respiratory rate 16 breaths/min, blood pressure 110/56 mm Hg, and oxygen saturation of 98% on room air. Physical examination revealed a well-nourished woman with jaundice in no acute distress, alert and oriented to person, place, time, and situation. She had notable scleral icterus. Abdominal examination was revealing of mild diffuse tenderness most profound in the right upper quadrant without distension, hepatosplenomegaly, or peritoneal signs, and no fluid shift wave. She had no asterixis or spider angiomata and no peripheral edema. Initial laboratory testing revealed (reference ranges provided parenthetically) an alanine aminotransferase (ALT) level of 2800 U/L (7 to 45 U/L), aspartate aminotransferase (AST) level of 2519 U/L (8 to 43 U/L), total bilirubin level 17.3 mg/dL (≤1.2 mg/dL), direct bilirubin level 9.5 mg/dL (0 to 0.3 mg/dL), and international normalized ratio (INR) 6.9 (0.9 to 1.1). The initial alkaline phosphatase level was 206 U/L (35 to 104 U/L). The lactate dehydrogenase (LDH) level was 569 U/L (122 to 222 U/L), lipase level 72 U/L (12 to 61 U/L), creatinine level 0.5 mg/dL (0.59 to 1.04 mg/dL), white blood cell count 7.7×109/L ((3.4 to 9.6)×109/L), hemoglobin level 12.3 g/dL (11.6 to 15 g/dL), and platelet level 131×109/L ((157 to 371)×109/L). The blood glucose level was 118 mg/dL (70 to 149 mg/dL). Right upper quadrant ultrasound was performed, which revealed a thickened gallbladder wall measuring 7 mm with a small amount of pericholecystic fluid and positive sonographic Murphy sign but no dilation of intrahepatic ducts or common bile duct. Ultrasound noted a small hemangioma of the right hepatic lobe. Computed tomography of the abdomen and pelvis with intravenous (IV) contrast was also completed without evidence of hepatic nodules or abscesses.1.Which one of the following is the most likely etiology of this patient’s presentation?a.

Cholangitis

b.

Metastatic disease

c.

Alcoholic hepatitis

d.

Ischemic hepatitis

e.

Drug toxicity

Cholestasis is indicated by laboratory values with elevated direct bilirubin and alkaline phosphatase levels. The differential diagnosis for cholestatic jaundice is broad, and initial evaluation should include a detailed history and physical examination followed by ultrasound or abdominal computed tomography imaging.1Assy N. Jacob G. Spira G. Edoute Y. Diagnostic approach to patients with cholestatic jaundice. Patient history is crucial and should include all medications and supplements, alcohol use, and travel history. Imaging is important to assess the presence of bile duct dilation. If bile ducts are dilated, proceeding with endoscopic retrograde cholangiography may be both diagnostic and therapeutic such as in cases of bile duct stones or strictures. Imaging is important for distinguishing between intrahepatic or extrahepatic cholestasis. Intrahepatic causes of cholestatic jaundice may include drug-induced liver injury (DILI), alcoholic hepatitis, viral hepatitis, autoimmune hepatitis, or hepatic infiltration such as sarcoidosis or lymphoma.1Assy N. Jacob G. Spira G. Edoute Y. Diagnostic approach to patients with cholestatic jaundice. Extrahepatic causes are anatomical obstruction and include gallstones, bile duct strictures, and neoplasms (most commonly pancreatic carcinoma).

This patient’s acute presentation with right upper quadrant abdominal pain, fever, and jaundice is concerning for an infectious etiology. This combination of signs and symptoms is well known as the Charcot triad. A positive Murphy sign is specific for acute cholecystitis, which is rarely associated with jaundice. The presence of jaundice and fever raises concern for ascending cholangitis. Acute ascending cholangitis typically occurs in the setting of bile duct obstruction with cholestasis and causes an obstructive jaundice. Cholangitis can be associated with high biliary pressure, which damages hepatocytes. Hepatocyte injury can cause abscess formation, but hepatocyte necrosis is rare and transaminases are rarely elevated beyond 2- to 3-fold. In this case however, imaging does not reveal duct dilation or lesions concerning for abscess, which makes ascending cholangitis less likely. Another diagnosis to consider is acalculous cholecystitis, which is gallbladder inflammation in the absence of gallstones. This most commonly occurs in critically ill patients with sepsis or prolonged absence of oral intake with reduced gallbladder contraction. This would be unlikely in this patient who was previously healthy.

Metastatic disease can also cause jaundice and should be considered in the setting of this patient’s untreated melanoma. Metastases, particularly melanoma, may lead to jaundice caused by infiltration of the hepatic parenchyma. However, in metastatic disease this is more commonly an insidious onset with painless jaundice. Fever, chills, and an acute presentation are less likely to be secondary to slow growing tumor burden.

Alcoholic hepatitis can be seen in patients who consume 2 or more alcoholic beverages per day. Acute alcoholic hepatitis often presents with jaundice, fever, tender hepatomegaly, elevated transaminase levels, and abnormal INR. Transaminase levels in alcoholic liver disease are typically disproportionately elevated with AST levels twice as much as ALT levels. Important to note is that liver enzyme elevations in alcoholic liver disease rarely exceed 300 U/L. Therefore, acute alcoholic hepatitis alone is unlikely to explain the significant degree of transaminase elevation seen in this patient.

This patient’s significant elevation in liver enzyme levels is most concerning for viral hepatitis, ischemic hepatitis, or medication/drug-related hepatitis. Ischemic hepatitis is caused by decreased hepatic perfusion from various etiologies including shock, profound hypoxia, or vaso-occlusion due to thrombus, embolism, or sickle cell crisis. Hepatocyte necrosis as a result of ischemia will typically lead to serum transaminase levels above 2000 U/L. This is unlikely in this patient given hemodynamic stability and other history. Acute viral hepatitis will have a similar presentation of symptoms and laboratory findings. Risk factors include travel to endemic areas, illicit drug use, or contact with contaminated food (such as shellfish) or water for hepatitis A. Infectious etiologies require laboratory diagnosis or exclusion. She does, however, take multiple medications and herbal supplements that increase her risk of DILI.

Over the next 20 hours after admission, the patient became obtunded and responsive to painful stimuli only.2.Which one of the following criteria best support this patient’s diagnosis of acute liver failure?a.

Acute onset of liver enzyme elevation

b.

Severe liver injury, hepatic encephalopathy, and elevated INR

c.

Alcohol use with liver injury but no evidence of chronic liver disease

d.

Progressive jaundice

e.

Acute decline in mental status

One of the diagnostic criteria for acute liver failure is the acute onset of liver enzyme elevation. As previously discussed, many situations can cause significant elevation in liver enzyme levels but may not always necessarily coincide with acute liver failure. The diagnostic criteria for acute liver failure includes acute liver injury, coagulopathy, and encephalopathy. As seen in this patient, progression to acute liver failure in less than 7 days is classified as hyperacute liver failure while progression in 7 to 21 days and in 22 to 26 days is classified as acute and subacute liver failure, respectively. Significant alcohol use is associated with both acute alcoholic hepatitis and chronic liver disease, but this history alone does not explain this patient’s diagnosis of acute liver failure. Worsening jaundice can be a sign of progressive liver failure. However, this is not specific and prehepatic causes such as hemolysis as well as posthepatic causes such as bile duct obstruction, which was excluded in this patient, can all present with worsening jaundice.

A decline in mental status can represent onset of hepatic encephalopathy, but this must be associated with additional manifestations of liver dysfunction to be concerning for acute liver failure. Hepatic encephalopathy can have a wide range of presentations and may manifest as a subtle decline in mental baseline with disorientation and confusion or as severe with somnolence or comatose state. The degree of encephalopathy present does not correlate with serum ammonia levels. The patient was diagnosed with hepatic encephalopathy and met diagnostic criteria for acute liver failure.3.Which one of the following is the best next step in management?a.

Transfer to an intensive care unit for supportive measures

b.

Initiate continuous renal replacement therapy

c.

Initiate broad-spectrum antibiotics

d.

Initiate fluid resuscitation

e.

Initiate symptomatic control with morphine

Acute liver failure is associated with rapid decompensation and high mortality. Therefore, it is crucial that these patients be managed in an intensive care unit at a hospital with liver transplant capabilities. These patients often become hypotensive despite fluid resuscitation and require vasopressor support. N-acetylcysteine (NAC) is used most notably for acetaminophen toxicity, but it is also indicated in acute liver failure of uncertain etiology and has been found to improve survival when administered early in the course of disease.2Lee W.M. Hynan L.S. Rossaro L. et al.Acute Liver Failure Study Group
Intravenous N-acetylcysteine improves transplant-free survival in early stage non-acetaminophen acute liver failure. This patient does not currently have evidence of acute renal failure, and first-line treatment of hyperammonemia has not been trialed yet, such as lactulose, so continuous renal replacement therapy is not the best next step. Although patients with acute liver failure are at increased risk of infections because of a multitude of factors including an inability to protect their airway, bacterial translocation, and the need for invasive catheters, prophylactic antibiotics without localizing evidence of infection have not been found to improve survival.3Rolando N. Gimson A. Wade J. Philpott-Howard J. Casewell M. Williams R. Prospective controlled trial of selective parenteral and enteral antimicrobial regimen in fulminant liver failure. Patients with acute liver failure are at risk of becoming markedly volume overloaded, and fluid intake and output should be strictly monitored. Intravenous fluids, administered for hypotension or included with IV medications, should be given judiciously with prompt initiation of vasopressors if needed. Lastly, it is important to conscientiously avoid both hepatotoxic and nephrotoxic drugs. Acute liver failure leads to renal failure in 55% of patients, so medications such as morphine and ibuprofen should be avoided.4Renal failure in acute liver failure.

The patient was tachycardic but remained hemodynamically stable. Lactulose enemas were initiated, and she was transferred to the medical intensive care unit. Shortly afterward, she required intubation for airway protection.

Ultimately, treatment of acute liver failure is centered around expedient and appropriate identification of the underlying cause. Results of infectious work-up including testing for tick-borne diseases (Anaplasmosis, Lyme disease, ehrlichiosis and babesiosis), viral hepatitis testing, and human immunodeficiency virus, Epstein-Barr virus, cytomegalovirus, and bacterial cultures were all negative. Liver biopsy was performed and revealed findings consistent with massive liver necrosis. She was diagnosed with immune checkpoint inhibitor (ICI)–induced hepatitis due to nivolumab, a programmed cell death protein-1 (PD-1) receptor inhibitor.4.Which one of the following is the most likely mechanism of this patient’s acute liver injury?a.

Cytokine storm causing shock liver

b.

Immune checkpoint inhibitor toxicity due to T-cell activation

c.

Inhibited cytochrome P450 with increased susceptibility to alcohol toxicity

d.

Adverse drug reaction inducing hepatocyte autophagy

e.

Drug-induced liver injury due to direct hepatotoxicity

In acute liver failure, understanding the mechanism of injury is extremely important in determining an appropriate and expedited treatment plan. Immunotherapy (including PD-1/PDL-1 inhibitors such as nivolumab) can trigger immune responses other than the ideal treatment effect, but not via cytokine storm, leading to autoimmune complications such as colitis, thyroiditis, adrenal insufficiency, and hepatitis.5Ramos-Casals M. Brahmer J.R. Callahan M.K. et al.Immune-related adverse events of checkpoint inhibitors. Nivolumab inhibits the PD-1 checkpoint protein, which encourages a T-cell antitumor response. This T-cell activation can also lead to hepatocyte damage and hepatic necrosis. Immune checkpoint inhibitor–induced hepatitis was favored over herbal supplement–induced hepatitis on the basis of her acute presentation and exposure history. She took multiple supplements frequently without recent changes, which would make acute liver failure unlikely to be caused by supplements she had previously tolerated well. Herbal supplement–induced liver injury can lead to progressive liver failure, but more commonly patients will recover after cessation of the supplement. This patient’s recent exposure to nivolumab with ongoing deterioration is more suggestive of ICI-induced hepatitis with a suspected mechanism of T-cell activation leading to progressive liver damage.6Regev A. Avigan M.I. Kiazand A. et al.Best practices for detection, assessment and management of suspected immune-mediated liver injury caused by immune checkpoint inhibitors during drug development. Immune checkpoint inhibitors do not lead to hepatotoxicity through cytochrome P450 inhibition. Many other medications are known to affect P450 metabolism and should be thoroughly considered in this patient with known herbal supplement and alcohol use. Mechanisms of injury from hepatocyte autophagy and direct drug injury are also separate from the indirect hepatic injury caused by ICIs.5.Which one of the following is the best next step in management?Plasmapheresis removes circulating autoantibodies. Plasmapheresis and intravenous immunoglobulins are useful in certain autoimmune conditions, but are not recommended for ICI-induced hepatitis. The role of corticosteroids in acute liver failure is controversial. Stress doses may be indicated in cases of septic shock despite fluid resuscitation and vasopressors, but they have also been found to increase the risk of sepsis and thus are not typically recommended. However, in the case of ICI-induced hepatitis, treatment with high-dose corticosteroids should be initiated early. Specifically, when liver enzyme levels are more than 5 times the upper limit of normal (ULN) or bilirubin levels are more than 3 times the ULN, corticosteroids with a methylprednisolone IV or oral equivalent of 1 to 2 mg/kg per day should be given with permanent discontinuation of the checkpoint inhibitor.7Nadeau B.A. Fecher L.A. Owens S.R. Razumilava N. Liver toxicity with cancer checkpoint inhibitor therapy. If the patient does not respond to high-dose corticosteroids, then a second immunosuppressive agent (ie, disease-modifying antirheumatic drugs) may be required. Colchicine has significant anti-inflammatory effects, but would not be useful in managing this patient’s acute liver failure.

The patient was not deemed to be a liver transplant candidate owing to a history of metastatic melanoma. Her hospital course was further complicated by hemorrhagic shock after liver biopsy, and she was managed with massive transfusion protocol. Continuous renal replacement therapy was initiated for volume removal. She was treated with high-dose steroids but remained persistently hypotensive, and volume removal was not possible. Ultimately, her family elected for compassionate extubation and transitioning her care to focus on her comfort only.

DiscussionWhen a patient has elevated liver enzyme levels, hepatic dysfunction, and coagulopathy in the absence of chronic liver disease, a diagnosis of acute liver failure must be considered. One must maintain a broad differential while quickly evaluating the potential cause, as treatment varies greatly depending on the underlying etiology and mortality is high. The approach to determining the most likely underlying etiology of acute liver failure should consider viral hepatitis, DILI, and acute ischemia. Once the commonest etiologies, that is, acetaminophen DILI and infections, are excluded, autoimmune conditions and other DILI should be considered.8Nonacetaminophen drug-induced acute liver failure. Ultimately, the diagnosis of DILI is challenging as extensive evaluation is required to make a diagnosis of exclusion and potential offending agents must all be discontinued, which makes confirming the diagnosis challenging as well. Liver biopsy may be pursued, but findings are often nonspecific with findings of active hepatitis, areas of necrosis, and occasionally portal fibrosis.9De Martin E. Michot J.M. Papouin B. et al.Characterization of liver injury induced by cancer immunotherapy using immune checkpoint inhibitors.Treatment of acute liver failure includes supportive measures in an intensive care unit with liver transplant capabilities. Broad-spectrum antibiotics are not necessary unless there is a high suspicion of infection. Immune checkpoint inhibitor–induced hepatitis rarely occurs with anti–PD-1 monoclonal antibody therapy and typically occurs within 8 to 12 weeks of initial treatment.10Tian Y. Abu-Sbeih H. Wang Y. Immune checkpoint inhibitors-induced hepatitis. Immune checkpoint inhibitor–induced hepatitis-specific treatment is based on the grade of liver enzyme elevation. Grade 1 is defined as AST or ALT levels 3 times the ULN, with total bilirubin levels 1.5 times the ULN. In grade 1, alcohol cessation is recommended but treatment with immunotherapy can be continued if the patient remains asymptomatic. Grade 2 is AST or ALT levels 3 to 5 times the ULN, with total bilirubin levels 1.5 to 3 times the ULN. Grade 2 treatment consists of holding ICI and treating with oral prednisone. If transaminase levels decrease to grade 1 or less without requiring ongoing steroids, ICI may be reintroduced. Grade 3 is defined as AST or ALT levels greater than 5 times the ULN, with total bilirubin levels greater than 3 times the ULN. Grade 4 is defined as AST or ALT levels greater than 8 times the ULN. Treatment of grade 3 and grade 4 includes discontinuation of ICI, initiation of IV corticosteroids, and performing a liver biopsy. In patients with grade 3 and 4 toxicity who do not respond to steroids, a second immunosuppressive agent may be required and treatment with mycophenolate should be considered.11Grover S. Rahma O.E. Hashemi N. Lim R.M. Gastrointestinal and hepatic toxicities of checkpoint inhibitors: algorithms for management.Potential Competing Interests

The authors report no competing interests.

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Renal failure in acute liver failure.

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Am Soc Clin Oncol Educ Book. 38: 13-19Article InfoFootnotes

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Identification

DOI: https://doi.org/10.1016/j.mayocp.2022.01.017

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© 2022 Mayo Foundation for Medical Education and Research

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