Hepatocellular carcinoma (HCC) is a malignant tumor with increasing morbidity and mortality worldwide (1). Immune checkpoint inhibitors (ICIs) show potential in the treatment of HCC, but their use may be accompanied by the risk of immune-related adverse events (irAEs). Studies have shown that HCC patients treated with ICIs have a similar overall incidence of irAEs but a higher risk of liver-specific irAEs compared to patients with other malignancies (2).

Adrenal crisis, also known as acute adrenal cortical insufficiency or Addison’s crisis, is a relatively rare type of immune - related adverse event (IrAE). Its clinical manifestations may include fever, anorexia, nausea, vomiting, abdominal pain, diarrhea, lethargy, tachycardia, hypotension, shock, and even coma. Laboratory tests often show reduced plasma cortisol levels, along with electrolyte abnormalities such as hypoglycemia, hyponatremia, and hyperkalemia. Timely recognition and treatment of adrenal crisis is crucial, otherwise it may seriously threaten the patient’s life (3).

This report presents a case of HCC patient with typical clinical manifestations of adrenal crisis after receiving targeted combined immunotherapy. Thanks to the timely diagnosis and active rescue efforts by the multidisciplinary team (MDT), especially the rapid supplementation of glucocorticoids, the patient’s condition was effectively controlled. This is the first case of adrenal crisis successfully treated in our department, and the successful management of this case highlights the importance of recognizing endocrine crisis induced by ICIs. In the diagnosis of hepatocellular carcinoma patients receiving targeted combined immunotherapy, special attention should be paid to identify septic shock and adrenal crisis in order to avoid misdiagnosis or omission of diagnosis.

Approximately 30 minutes after the start of piperacillin - tazobactam infusion, the patient developed an abrupt onset of fever, with the body temperature rising rapidly to 39°C, accompanied by severe chills that caused the entire body to shiver. Intense nausea and continuous retching were also present, although no vomiting occurred at that time. Suspecting a drug - related adverse reaction, the medical team promptly suspended Piperacillin - tazobactam and switched to Levofloxacin for anti - infection.

After one hour, the patient’s chills gradually subsided, and the body temperature decreased to 38°C. The nausea and retching also improved. However, laboratory tests revealed abnormal results in Table 2. The procalcitonin (PCT) were elevated to 0.17 ng/ml (reference range: 0-0.05 ng/mL), suggesting a possible inflammatory response. Interleukin-6 (IL-6) was significantly elevated to 1227.00 pg/ml (reference range: 0–7 pg/mL), suggesting that an immune-mediated process was underway. Blood glucose level decreased to 2.79 mmol/L (reference range: 3.9-6.1 mmol/L) and sodium level was 130.9 mmol/L (reference range: 137–147 mmol/L), which were both below the normal range. Although routine blood tests showed no significant changes in white blood cell (WBC) 3.9*10⁹/L (reference range: 3.5-9.5*10⁹/L), neutrophil percentage 58.7% (reference range: 40-75%), and C-reactive protein (CRP) 4.06 mg/L (reference range: 0–8 mg/L), these abnormal biochemical indicators were still cause for concern.

Later in the evening, at 21:00, the patient’s condition deteriorated again. The patient had three episodes of watery diarrhea, each of small volume. Subsequently, the patient vomited twice, with the vomitus consisting of gastric contents and previously ingested oral medications. The body temperature remained at 38°C, without chills, but with minimal sweating. Physical examination at this time showed that the patient was still conscious but in a relatively weakened mental state. The blood pressure was 110/70 mmHg, the heart rate was 65 beats per minute, the pulse oxygen saturation was 96%, and the respiratory rate was 20 breaths per minute. To address the deteriorating condition, the medical team provided oxygen inhalation and initiated fluid replacement therapy while closely monitoring the blood pressure.

On August 17, 2024, at 1:00 a.m., the patient experienced a more critical situation. The patient suddenly developed acute abdominal pain with severe pain in the lower back and limbs. The patient clearly stated that the pain was not metastatic right lower abdominal pain, and there were no symptoms of shortness of breath, chest tightness, cough, or dyspnea. Body temperature remained at 39 °C. Physical examination showed that the patient was alert but in severe pain, pale and with a distressed expression. The skin was slightly moist with no blotches or petechiae. Breath sounds were diminished in both lungs, with no obvious dry or wet rales. Bowel sounds were normal, but there was marked percussion pain in the renal region. The abdomen was rigid with marked periumbilical tenderness and rebound pain. McBurney’s point was not indurated and shift retardation remained positive. There was no edema of the lower extremities. Cardiac monitoring showed a marked drop in blood pressure to 70/42 mmHg, a heart rate of 79 beats per minute, a pulse oximetry of 95%, and a respiratory rate of 18 breaths per minute. The electrocardiogram showed normal sinus rhythm with no significant arrhythmias and consistent blood pressure readings on both sides. Despite fluid resuscitation with crystalloid and colloid fluids, the patient’s blood pressure remained low, prompting the medical team to urgently contact a multidisciplinary consultation, including endocrinology, intensive care medicine, and gastroenterology.

After a thorough review of the patient’s case features (Figure 2) and in-depth multidisciplinary discussion, we zeroed in on two primary diagnoses: 1. adrenal crisis (the patient had adrenal insufficiency and had been on ICIs); and 2. septic shock (the patient had a well-defined infection, primarily peritonitis). Based on the laboratory tests present at the time (shown in Table 2), our detailed differential between sepsis and adrenal crisis (shown in Table 3) still did not rule out either diagnosis. We did more detailed laboratory tests as shown in Table 2. It is worth mentioning that we sent blood bacterial cultures for testing multiple times but did not obtain positive results. Therefore, looking back on the entire treatment process, we further confirmed the diagnosis of adrenal crisis.

Once adrenal crisis was taken into account, we immediately administered 100 mg of hydrocortisone, adequate fluid resuscitation, and vasopressor medication to maintain blood pressure in accordance with the treatment guidelines. The patient’s blood pressure fluctuated at 80-90/55–65 mmHg during the night. In addition, due to definite peritonitis in the patient, there were markedly elevated PCT (20.3 ng/mL) and IL-6 (1621.00 pg/mL), as well as decreased WBC (3.27* 10⁹/L), a neutrophil percentage of 78.4%, and a CRP of 8.52 mg/L, meropenem 1 g q8h was still administered for anti-infective. After confirming the supplementation of hydrocortisone, the COR value we remeasured the next day was 1261 nmol/L and ACTH was less than 1.5 pg/ml. We continued to administer 200 mg of hydrocortisone for 24 hours for anti-infection and antihypertensive treatment. On August 18, 2024, the patient’s blood pressure stabilized at 120/71 mmHg, and we discontinued dopamine. On August 19, 2024, the patient’s blood pressure was stable. Due to ascites, a diuretic was added. Hydrocortisone was reduced to 100 mg for intravenous infusion every day and anti-infection treatment was administered. We conducted abdominal and adrenal magnetic resonance imaging (MRI) as well as pituitary magnetic resonance imaging for the cause. No obvious abnormalities were found in the result (Figures 3, 4). Three days later, it was changed to oral hydrocortisone acetate tablets 40 mg bid. At the same time, the antibiotics were reduced to oral levofloxacin tablets 0.5 g qd, levothyroxine sodium tablets 100 μg qd, ursodeoxycholic acid tablets 250 mg tid and concentrated sodium treatment were continued. On August 28, 2024, the COR was reexamined at 338 nmol/L and the ACTH was less than 1.5 pg/ml. After hormone supplementation, the patient no longer experienced symptoms.

We conducted a six-month follow-up, during which the patient had a good appetite, improved fatigue, and a stable physical condition. Relevant laboratory and clinical indicators were stable, such as COR 102 nmol/L, blood glucose 4.9 mmol/L, and blood sodium 137.1 mmol/L (March 9, 2025), which indicated that the patient’s complex condition was under positive control. The patient continued to take hydrocortisone acetate tablets, levothyroxine tablets, and polyene phosphatidylcholine, and discontinued treatment with targeted drugs and ICIs.

This case involves a patient with liver cancer who had a history of “hepatitis B” and “Hashimoto’s thyroiditis”, as well as a period of hyponatremia. In addition, the patient had a history of immune checkpoint inhibitor treatment and experienced multiple ICI - related liver injuries. The patient’s general condition was fair, but examinations indicated the presence of peritonitis and adrenocortical insufficiency, with no prior history of steroid (glucocorticoid) use. The next day after admission, the patient developed a fever. After ruling out adverse reactions caused by antibacterial drugs, the patient subsequently experienced persistent fever, loss of appetite, nausea, vomiting, abdominal pain, diarrhea, listlessness, tachycardia, hypotension, and shock. These symptoms are not specific. Especially considering the patient had decompensated liver cirrhosis complicated by intra - abdominal infection, similar symptoms could also occur when the disease progresses to septic shock. However, laboratory tests showed a decrease in plasma cortisol levels, along with electrolyte abnormalities such as hypoglycemia and hyponatremia, which caught our attention. After immediately administering hydrocortisone, the patient’s vital signs gradually stabilized. At the time of the patient’s fever we took blood cultures and ascites cultures, both of which were negative. Therefore, we diagnosed this series of changes in this patient as adrenal crisis. This resuscitation process was also very challenging for the hepatologists.

Although the patient underwent surgery, TACE, and small molecule targeted drugs, but because the targeted drugs are multi-target tyrosine kinase inhibitors, which mainly play an anti-tumor effect by inhibiting various enzymes related to tumor growth and angiogenesis, according to our investigation, there is insufficient evidence that these drugs and treatments are related to adrenal insufficiency (4, 5). However, the incidence of adverse events associated with the use of immune checkpoint inhibitors is on the rise. Randomized controlled trials have demonstrated an incidence of any IRAE in 54–96% of those treated with ICI therapy (6). In a comprehensive meta-analysis that did not incorporate any hepatocellular carcinoma (HCC) trials, the most commonly affected target organs by immune-related adverse events (irAEs) during cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) inhibition were the skin (44%) and the gastrointestinal tract (35%) (7). The endocrine glands and the liver were affected in 6% and 5% of cases, respectively. In another meta-analysis encompassing nearly 3,000 treated patients, the most frequently targeted organs by irAEs during programmed death-1 (PD-1) or programmed death-ligand 1 (PD-L1) inhibition were the skin (pruritus 10%, rash 11%), the gastrointestinal tract (diarrhea 11%), and the thyroid (hypothyroidism 7%) (8). Endocrine disorders include hypothyroidism, hyperthyroidism, pituitary inflammation, primary adrenal insufficiency (PAI), and insulin-deficient diabetes (9). Sintilimab (10) and Camrelizumab (11) and TA regimen (atilizumab combined with bevacizumab) (12) are used as first-line drugs for the treatment of hepatocellular carcinoma, and they are humanized anti-programmed death receptor 1 (PD-1) monoclonal antibodies. They mainly work by blocking the binding of PD - 1 to its ligand PD - L1, relieving the inhibitory effect of the PD - 1 pathway on T cells, thereby activating T - cell functions and enhancing the immune system’s attack on tumor cells (13–15). We searched for case reports of adrenal crisis due to tislelizumab applied to other tumors in Table 4 (16–18), like lung squamous cell carcinoma and bladder cancer patients. It mostly occurs during the middle to late stages of treatment (median 7 cycles) or 5 months after discontinuation of treatment. All cases require permanent discontinuation of immunotherapy, and 5/6 patients suffer irreversible damage to adrenal function, requiring long-term hormone replacement.

Adrenal crisis is a relatively rare and serious immune checkpoint inhibitor (ICI)-related adverse event that usually occurs in patients with adrenocortical insufficiency. According to the Common Terminology Criteria for Adverse Events (CTCAE), adrenal cortical insufficiency is usually a grade 1–2 immune - related adverse event (irAE), while adrenal crisis is a grade 3–4 irAE (19). A large meta - analysis of 160 clinical trials involving 40,432 patients reported that among patients using ICIs, the estimated incidence rates of adrenal cortical insufficiency and hypophysitis were 2.43% and 3.25% respectively. Using a random - effects model, the incidence rates of all - grade and severe - grade adrenal cortical hypofunction were 2.43% (95% CI, 1.73% - 3.22%) and 0.15% (95% CI, 0.05% - 0.29%) (20). Adrenal cortical insufficiency usually presents with some non - specific clinical symptoms, including fatigue, anorexia, nausea, abdominal pain, and diarrhea (21). These symptoms are difficult to distinguish from the complications of liver cancer patients. The symptoms of adrenal crisis are more severe. Based on the above - mentioned symptoms, there may be listlessness, tachycardia, hypotension, shock, and even coma. These symptoms are difficult to distinguish from those of septic shock. Therefore, laboratory tests are essential for the diagnosis of adrenal crisis, and attention should be paid to the examination of cortisol and electrolytes.

Immune checkpoint inhibitor-induced adrenal insufficiency (AI) can be divided into primary AI (adrenocortical destruction) and secondary AI (ACTH deficiency due to pituitary failure) according to the site of the lesion, and the mechanisms and characteristics of the two are significantly different. Secondary AI is the most common type of ICI-associated AI, mainly caused by ICI-induced pituitary inflammation, and its pathogenesis is closely related to autoimmune response (22), especially seen with CTLA-4 inhibitors (e.g., ipilimumab) and combination therapies (CTLA-4 + PD-1/PD-L1 inhibitors). Preclinical and clinical evidence supports this mechanism (23, 24): anti-CTLA-4 monoclonal antibody induces pituitary inflammation through complement-mediated cytotoxicity in a mouse model; autopsy studies have shown strong CTLA-4 expression in the pituitary gland of the patients as well as pathological features consistent with both type II (antibody-mediated) and type IV (T-cell-mediated) hypersensitivity; and antipituitary hormone antibodies (e.g., anti-ACTH antibodies) are detected in the patient serum. Pituitary inflammation leads to insufficient ACTH secretion (incidence up to 75%), which in turn causes atrophy of the adrenocortical zona fasciculata and decreased cortisol synthesis, manifesting as hypocortisolism with low/normal ACTH, often coexisting with other anterior pituitary hormone deficiencies; recovery of the ACTH axis function is rare, and long-term glucocorticoid replacement is usually required.

In contrast, primary AI is relatively rare (~0.7% overall, up to 4.2% with combination therapy), and the mechanism is that ICI (especially with combination therapy) triggers autoimmune adrenal inflammation that directly destroys the adrenal cortex (25). Due to the low incidence of PAI associated with ICPis, the number of cases is small, the follow-up is short, and the characteristics of the population and the risk factors have not yet been clarified. Known risk factors include a history of comorbid autoimmune disease, use of CTLA-4 inhibitors, and chronic kidney disease stage 3 or higher. Drug dosage may also influence morbidity, with studies showing a higher risk of PAI at doses of ibritumomab above 5 mg/kg (26).This is similar to traditional Addison’s disease, resulting from adrenocortical destruction mediated by T cells, etc. ICI may break tolerance to adrenal autoantigens (e.g.,21-hydroxylase), involving susceptibility genes (e.g. CTLA-4, PDCD1) and specific HLA haplotypes (e.g., HLA-DR3-DQ2) (27, 28). Primary AI results in a severe deficiency in both cortisol and saline corticosteroid (aldosterone) secretion, which manifests as low cortisol with high ACTH, and characteristic symptoms include malaise, hypotension, nausea and vomiting, hyponatremia, hyperkalemia, and hyperpigmentation of the skin and mucous membranes. Adrenocortical destruction is usually irreversible and requires lifelong combined replacement of physiologic doses of glucocorticoids and saline corticosteroids (fludrocortisone) and strict patient education in stress management. The key points of differentiation between the two are: secondary AI originating from pituitary inflammation (lesion in the pituitary gland, ACTH deficiency), with biochemical hallmarks of low cortisol + low/normal ACTH, electrolyte disturbances mainly hyponatremia, no hyperpigmentation, usually preserved saline corticosteroid function, and rare restoration of the ACTH axis; and primary AI originating from adrenal inflammation (lesion in the adrenal gland), with biochemical hallmarks of low cortisol + high ACTH, characterized by low sodium and high potassium and hyperpigmentation, with salicorticoid deficiency requiring replacement, largely irreversible (25).

The American Society of Clinical Oncology (ASCO) guidelines (29) state that routine endocrine examinations should be performed on patients receiving ICI treatment to assess endocrine glands or organs, which is of great importance. We firstly found the diagnosis of adrenal cortical hypofunction through the examination of the patient’s cortisol and ACTH, which provided an effective clue for our diagnosis. Several studies have shown that a history of prior adrenal crisis is a predisposing factor for recurrent adrenal crisis in patients with adrenocortical insufficiency (31). In reviewing the patient’s medical history, we found that the patient had an episode of hyponatremia with impaired consciousness 5 months prior to admission, when the serum cortisol (8:00 a.m.) level was 117 nmol/L (reference range: 166–507 nmol/L), and the corresponding ACTH level was 14.3 pg/ml pg/mL (reference range: 7.2-63.3 pg/mL), which suggested that the patient already had adrenocortical insufficiency at that time, and what we could not confirm was whether the patient’s impaired consciousness was a neurologic manifestation of irAEs or due to hyponatremia. However, the emergency physician did not realize that this could be related to irAEs and did not supplement hydrocortisone in a timely manner, which may be another important reason for the development of this crisis and needs to be brought to the attention of emergency physicians as well as physicians in related specialties.

The timing of IRAEs varies, typically occurring within weeks to months of treatment commencement. The median time to onset of moderate to severe endocrine disorders treated with ipilimumab was 1.75–5 months, and that treated with PD-1 inhibitors was 1.4-4.9 months (30, 31). Moreover, adrenal dysfunction may occur at any time during or even after ICIs (32). Importantly, this irAE can occur several months after discontinuing an ICI (33). An increasing number of clinical cases have proven that endocrine diseases such as delayed - onset adrenal crisis (AC) can occur after the termination of ICI treatment, which also demonstrates that the anti - tumor effect of ICIs can be expressed in the body for a long time (34, 35). Therefore, even after the discontinuation of ICIs, it is recommended to always be vigilant about the possibility of irAEs.

In addition, in this patient, we found that apart from receiving 8 cycles of PD - 1 treatment, there were no other related causes and predisposing factors. Although the drug had been discontinued for 4 months, the damage seemed to be persistent. Patients with pre-existing autoimmune diseases have a higher risk of autoimmune disease deterioration and may also experience unrelated irAEs (36). The patient has an autoimmune disease basis for Hashimoto’s thyroiditis, which is a high risk factor.

Since the patient also had a decrease in thyroid hormone levels, we considered the possibility of immune - related hypophysitis (irH). It is defined as the occurrence of functional defects in one or more pituitary axes in patients receiving ICI treatment, with or without mild pituitary MRI abnormalities (37, 38).The diagnostic criteria proposed by Nguyen (39) et al. include central adrenal cortical insufficiency or central hypothyroidism, and MRI findings consistent with irH, or the presence of symptoms of central adrenal cortical insufficiency and hypothyroidism (such as headache or fatigue), but no abnormalities were found on MRI or MRI was not performed. We completed the detection of other hormone levels, with the results as follows: growth hormone (0’) 11.60 ng/ml (elevated), 17α-hydroxyprogesterone 0.48 ng/ml, follicle-stimulating hormone 8.23 mIU/ml, luteinizing hormone 13.19 mIU/ml (elevated), estradiol 38.69 pg/ml, progesterone 0.08 ng/ml, testosterone 4.29 ng/ml, prolactin 35.89 ng/ml (elevated), sex hormone-binding globulin 34.31 nmol/L, free testosterone index 43.39%, and anti-Müllerian hormone 2.460 ng/ml. None of the aforementioned indicators showed clinically significant abnormalities. Unfortunately, as of the submission of this manuscript, considering safety and the patient’s autonomous wishes, the ACTH stimulation test was not performed on the patient. Research shows that 77% of patients with IRH have pituitary enlargement, stalk thickening, and homogeneous or heterogeneous contrast enhancement on MRI, while 23% - 33% of patients show no abnormalities on MRI (24). We also conducted imaging examinations of the pituitary and adrenal glands, and no special findings were observed in this patient. Studies have found that compared with CTLA - 4 inhibitors, pituitary induced by PD - 1/PD - L1 inhibitors may lack typical pituitary enlargement and present a normal pituitary morphology (29, 39). We performed an MRI of the pituitary gland and adrenal glands in this patient, and the results were unremarkable as shown in Figures 3, 4. In general, when endocrine examinations suggest central adrenal cortical hypofunction, hormone replacement therapy should not be delayed due to waiting for pituitary MRI results.

In terms of treatment, the key to treating adrenal crisis is to rapidly replenish glucocorticoids and correct electrolyte disorders (40). Usually, it is necessary to immediately inject hydrocortisone intravenously, and then continue infusion or give maintenance doses regularly. At the same time, it is necessary to actively replenish normal saline to correct dehydration and electrolyte imbalance. During the treatment process, it is also necessary to actively control predisposing factors such as infections and provide systemic supportive treatment. When an immune - therapy - related adrenal crisis occurs, in addition to supportive fluid therapy, an initial intravenous or intramuscular bolus injection of 100 mg of hydrocortisone is required, along with continuous intravenous infusion of 200 mg of hydrocortisone once every 24 hours (per day) or 50 mg of hydrocortisone every 6 hours (or 50 mg, four times a day). The recommended duration is 24–48 hours. Alternatively, after the initial bolus dose, a continuous infusion of 200 mg/24 h can be used until the patient can take hydrocortisone orally (3). It should be noted that dexamethasone is not a suitable substitute for glucocorticoids because it lacks mineralocorticoid activity. Our patient had no history of underlying endocrine diseases such as diabetes, so there were no specific restrictions on the dosage of cortisol. For diabetic patients, choosing an appropriate cortisol dosage to maximize benefits and reduce related side effects is a challenge. For adults, when the patient’s condition is stable, glucocorticoid replacement therapy should be the main treatment. Hydrocortisone can be selected and administered three times a day (or occasionally twice a day). For example, 10 mg can be taken immediately after waking up, 5 mg at noon, and 5 mg in the afternoon, or 15 mg after waking up and 5 mg at noon (40, 41). During subsequent follow - up, the dosage of hydrocortisone is gradually reduced according to the patient’s clinical manifestations, and blood pressure and recurrence of clinical symptoms are closely monitored. Both the rescue and treatment of this patient were conducted under endocrinologists’ guidance, with the overall treatment plan aligned with the core principles of standard guidelines. We recommend immediate consultation with endocrinologists for intervention and treatment guidance once adrenal crisis is suspected, followed by subsequent follow-up in the Department of Endocrinology. According to relevant guidelines or recommendations from NCBI, patients need to be on long-term hydrocortisone and monitored for COR. Additionally, patients will need to be educated on sick day rules and be provided with medical alert bracelets, and have high-dose corticosteroids for emergency purposes (9, 42).

There are several issues that require in-depth consideration. First, it has been suggested that the occurrence of irAEs may be a positive predictor of treatment response, and that there is a positive correlation between the occurrence of immune-related adverse events (irAEs) induced by immune checkpoint inhibitor (ICI) therapy and improved tumor response and survival rates (43). Theoretically, during the treatment with ICI, as the immune system’s tolerance to triggering irAEs decreases, its ability to recognize and kill cancer cells indeed increases. Before admission, we evaluated the patient’s liver cancer condition and found no metastatic or recurrent tumor lesions, indicating that the patient had a complete response to the immune checkpoint inhibitor treatment. We have followed up the patient for half a year after the occurrence of adrenal crisis (as of the time of publication) and have not found any signs of HCC recurrence. Therefore, it seems necessary to continue the treatment with immune checkpoint inhibitors. However, resuming the treatment with immune checkpoint inhibitors requires considering many factors. Currently, it is believed that after the disappearance of adverse reactions, it is necessary to comprehensively consider the previous tumor response, treatment duration, type and severity of toxicity, time of toxicity regression, availability of alternative therapies, the patient’s condition, and the patient’s acceptance before deciding whether to restart the trea. However, the recovery of the pituitary-adrenal axis is very rare (44, 45).

Second, current medical tests are unable to distinguish between immune-related and non-immune-related causes, and the lack of specific immunobiological markers makes it difficult for clinicians to detect irAEs (46). The management of ICI - related irAEs requires the collaboration of a multi - disciplinary team and timely assessment of the patient’s basic endocrine hormone levels. Before treatment with PD - 1/PD - L1 inhibitors, patients should be carefully questioned about their history of endocrine and autoimmune diseases, undergo reasonable baseline screening, regularly monitor changes in endocrine indicators, and be more vigilant about possible related symptoms and signs to detect and handle irAEs as early as possible. For the occurred irAEs, a prompt diagnosis should be made, and they should be graded according to the severity of the disease, followed by symptomatic treatment to relieve the discomfort of patients during the treatment process.

Third, for patients with chronic viral hepatitis, under the condition of strict monitoring of viral hepatitis, the efficacy of ICI treatment is not significantly different from that of uninfected patients, but it is still necessary to closely monitor and handle possible irAEs (32).

Last, the issue of the risk of HBV reactivation must be emphasized during the implementation of immunosuppressive therapy in hepatitis B patients. The APASL Clinical Practice Guideline (47) states that for HBsAg-positive patients, prophylactic antiviral therapy should be initiated immediately prior to the initiation of immunosuppressive therapy and continued until at least 6 to 12 months after the end of therapy. Prophylactic antiviral therapy should also be considered for anti-HBc-positive but HBsAg-negative patients who are receiving high-risk immunosuppressive therapy. Patients not receiving prophylactic antiviral therapy need to be closely monitored for HBV DNA levels and liver function markers, and antiviral therapy should be initiated as soon as HBV reactivation is detected. Therefore, it is indisputable that patients with hepatitis B-related hepatocellular carcinoma implementing immunosuppressive therapy should receive long-term antiviral therapy to avoid HBV reactivation.

In conclusion, although the diagnostic and treatment process of this case has many shortcomings, we hope that the report of this case will raise the awareness of related doctors about ICIs leading to adrenal crisis. When diagnosing and treating hepatocellular carcinoma patients receiving targeted combination immunotherapy, attention should be paid to differentiating septic shock from adrenal crisis to avoid misdiagnosis or omission.