Mild liver injury following withdrawal of long-term prednisone therapy: A case report

Abstract

BACKGROUND

Liver injury manifesting as hepatic enzyme abnormalities, has been occasionally identified to be a feature of primary or secondary Addison's disease, an uncommon endocrine disease characterized by adrenal insufficiency. There have been no more than 30 reported cases of liver injury explicitly attributed to Addison's disease. Liver injury resulting from adrenal insufficiency due to glucocorticoid withdrawal is exceptionally rarer.

CASE SUMMARY

A 42-year-old man presented with fatigue and mildly elevated transaminases. Laboratory investigations and imaging studies excluded common etiologies of liver injury. Based on the fact that the patient discontinued long-term therapy with prednisone approximately 2 weeks before he was found to have elevated transaminase levels and the observation that his cortisol was lower than the normal value, he was diagnosed as having hypertransaminasemia secondary to adrenal insufficiency caused by glucocorticoid withdrawal. The patient was infused intravenously with compound diisopropylamine dichloroacctate and compound glycyrrhizin, and his transaminase levels returned to normal after 1 week. Approximately 2 years later, the patient received hydroprednisone treatment for 2 days in an endoscopic sinus surgery. Eight days after he discontinued the hydroprednisone treatment, he developed symptoms reminiscent of glucocorticoid withdrawal syndrome. These symptoms resolved spontaneously after 1 week. Intriguingly, the patient did not develop hepatic dysfunction this time.

CONCLUSION

The present case, showing some unusual clinical features, highlights the importance of education of clinicians and patients to avoid improper discontinuation of glucocorticoid therapy and complete history taking for prompt recognition.

Key Words: Liver injury; Transaminase; Prednisone; Addison's disease; Adrenal insufficiency; Case report

Core Tip: This paper describes a rare case of mild hypertransaminasemia occurring following withdrawal of long-term prednisone therapy, a condition that is potentially underestimated and easily ignored. The presented case suggests that hypertransaminasemia caused by glucocorticoid withdrawal may have different features from hypertransaminasemia due to primary Addison's disease; the severity of adrenal insufficiency may be associated with the development of elevated transminases and their levels; and glycyrrhizin may be an option for patients with mild adrenal insufficiency due to glucocorticoid withdrawal who have planned to discontinue this hormonal therapy.

INTRODUCTION

Endocrine diseases, mainly diabetes, hypothyroidism, and hyperthyroidism, have been well recognized to be able to give rise to hepatic dysfunction[1]. Liver injury manifesting as mild hepatic enzyme abnormalities, has been occasionally identified to be a feature of Addison's disease (either primary or secondary), an uncommon endocrine disease characterized by adrenal insufficiency, since the first report of such association by Olsson et al[2] in 1990. Up to now, there have been no more than 30 reported cases of liver injury explicitly attributed to Addison's disease[3-7]. Liver injury caused by adrenal insufficiency due to glucocorticoid withdrawal, a common form of secondary Addison's disease, is even rarer and only two such cases are identified in the literature[5,8]. Due to the fact that Addison's disease often has a chronic course to allow the development of typical symptoms, while the course of adrenal insufficiency due to glucocorticoid withdrawal is often shorter, the latter may lack some typical symptoms of primary Addison's disease. On the other hand, the diverse side effects associated with prolonged use of glucocorticoid therapy, such as hypertension and electrolyte disorders, possibly mask the typical symptoms of primary Addison's disease[9]. Furthermore, untimely acquisition of history of glucocorticoid withdrawal may lead to a prolonged disease course and the development of some atypical symptoms such as jaundice, as in the case presented by Li et al[8], making the diagnosis more challenging. Given such potential distinct features of liver injury caused by primary Addison's disease and adrenal insufficiency due to glucocorticoid withdrawal, we herein report a case of mildly elevated aminotransferases following glucocorticoid withdrawal. In addition, we performed a review of the relevant literature to discuss this unusual condition in order to raise its awareness among clinicians.

CASE PRESENTATION

Chief complaints

A 42-year-old man was admitted to Zhengzhou People's Hospital, Zhengzhou, China on September 12, 2014 with fatigue for 10 days and elevated transaminases for 1 day.

History of present illness

The patient developed fatigue, decreased appetite, abdominal distention, and sweats 10 days before, with no fever, dizziness, palpitations, nausea, vomiting, diarrhea, melena, or weight loss. He visited the outpatient department of the same hospital 1 day before and was recommended to undergo a liver function test due to a past history of hyperthyroidism, which revealed elevated alanine aminotransferase (ALT) and aspartate aminotransferase (AST).

History of past illness

The patient had a history of hyperthyroidism due to Grave’s disease for 12 years but no hepatic dysfunction before, during, and after treatment with methimazole. He had a history of suspected pulmonary sarcoidosis that had no involvement of other organs for 2 years. He had been initially treated with prednisone 30 mg/day for suspected pulmonary sarcoidosis, which was gradually tapered to 5 mg/day and then discontinued approximately 2 weeks before. The patient denied taking any other medications that may lead to hepatic enzyme elevation.

Personal and family history

The patient had no remarkable personal or family history of similar illnesses. He denied any history of contact with infected patients or ill animals, or history of recent foreign travel.

Physical examination

The patient weighed 80 kg, and his height was 180 cm. His vital signs were as follows: Body temperature, 36.3 °C; blood pressure, 128/87 mmHg; heart rate, 72 beats/minute; respiratory rate, 21 breaths/minute. No significant positive signs were identified during physical examination.

Laboratory examinations

One day before the patient’s admission, a liver function test performed in the outpatient clinic of the same hospital revealed elevated ALT (125 U/L; normal range: 9-50 U/L) and AST (80 U/L; normal range: 9-50 U/L) levels. Laboratory tests performed after admission confirmed the elevation of ALT and AST, with no increase in other hepatic enzymes [total bilirubin: 12.1 μmol/L (normal range: 0-20 μmol/L); direction bilirubin: 5.0 μmol/L (normal range: 0-10 μmol/L); alkaline phosphatase: 97 U/L (normal range: 45-125 U/L); γ-glutamine transpeptidase: 20 U/L (normal range: 10-60 U/L); lactate dehydrogenase: 197 U/L (normal range: 80-240 U/L)]. Serology for hepatitis viruses A, B, C, and E, human immonodeficiency virus, Epstein-Barr virus, and cytomegalovirus was normal. Tests for autoantibodies including antinuclear antibody, anti-myeloperoxidase antibody, anti-protease 3 antibody, anti-liver cytosol antibody type 1, anti-liver/kidney microsomal antibody, anti-smooth muscle antibody, anti-mitochondrial antibody, antinuclear antibody, and anti-double-stranded DNA antibody were all negative. Other routine laboratory analyses, including blood test, urine test, fecal examination, coagulation function, renal function, thyroid function, blood glucose, erythrocyte sedimentation rate, C-reactive protein, and tumor markers, showed no significant findings except a marginal increase in carcinoembryoic antigen (5.73 ng/mL; normal range: 0-5 ng/mL) and activated partial thromboplastin time (32.7 seconds; normal range: 23-32 seconds). Suspicion for adrenal deficiency was raised due to the fact that the patient discontinued long-term prednisone therapy approximately 2 weeks prior to the development of elevated transaminases. Therefore, serum cortisol and adrenocorticotropic hormone (ACTH) were measured, which revealed that serum cortisol level was low (5.49 μg/dL; normal range: 8.7-22 μg/dL) while ACTH was in the normal range (25.41; normal range: 7.5-58 μg/dL).

Imaging examinations

Magnetic resonance imaging of the upper abdomen showed multiple small cysts (< 4 mm in diameter) in the right lobe of the liver, with no other major findings.

FINAL DIAGNOSIS

The patient was finally diagnosed with mild liver injury secondary to withdrawal of long-term prednisone therapy.

TREATMENT

The patient was infused intravenously with compound diisopropylamine dichloroacctate and compound glycyrrhizin for 1 week.

OUTCOME AND FOLLOW-UP

The patient’s ALT and AST levels returned to normal on September 21, 2014 (ATL: 32 U/L; AST: 24 U/L) after treatment with liver-protecting drugs for 1 week. He was discharged from the hospital on September 23, 2014.

Approximately 2 years later on June 10, 2016, the patient underwent endoscopic sinus surgery for mycotic maxillary sinusitis at another hospital. He received hydroprednisone 60 mg/day for 2 days during the perioperative period. Two days after he was discharged on June 10, 2016, he developed extreme fatigue, severe weakness, and sweats, symptoms highly suspected to be due to glucocorticoid withdrawal. Fortunately, these symptoms resolved spontaneously after 1 week. Of note, he did not develop hepatic dysfunction either before or after the presence of these symptoms. The patient is still healthy as of this writing.

DISCUSSION

It has been well established that endocrine diseases can lead to hepatic dysfunction; compared to diabetes and hypothyroidism, Addison's disease, especially adrenal insufficiency caused by improper glucocorticoid withdrawal, is a rare cause of hypertransaminasemia[1]. Our patient had a 12-year history of hyperthyroidism, to which his hypertransaminasemia was easily attributed. However, the patient had never had transaminase elevation during the whole course of his hyperthyroidism and the use of anti-thyroid drug (methimazole). More importantly, his thyroid function test was normal. Based on the fact that he discontinued long-term therapy with prednisone 2 days before he was found to have elevated ALT and AST levels and the observation that his cortisol was lower than the normal value, he was diagnosed with hypertransaminasemia secondary to adrenal insufficiency caused by glucocorticoid withdrawal. Besides the case presented here, a literature search identified two other such cases, one reported by Vafaeimanesh et al[5] and the other by Li et al[8] (Table 1).

Table 1 Characteristics of reported cases of liver injury following adrenal sufficiency due to glucocorticoid withdrawal.

Ref.	Age (year)	Sex	Glucocorticoid used	Duration of glucocorticoid use	Clinical manifestations	Electrolyte disturbance	Abnormal hepatic function indexes at admission	Initial serum cortisol at 8:00 am/ACTH levels	Time from symptom onset to diagnosis	Treatment	Outcome
Li et al[8]	65	Female	Prednisone 20-40 mg/day	> 2 years	Nausea, vomiting, fatigue, anorexia, pitting edema of lower limbs, jaundice	Hypokalemia, hyponatremia, hypochloremia	Increased ALT (89 U/L; normal range: 3-35 U/L), AST (174 U/L; normal range: 13-35 U/L), total bilirubin, and direct bilirubin and decreased albumin	Cortisol: 42.12 (118.6-618) nmol/L; ACTH: 1.23 (< 10.2) pmol/L	6 months	Intravenous hydrocortisone 30 mg/d for 5 days, followed by oral methylprednisolone 6 mg/day	Fully recovered and remained healthy on hormone therapy over 1-year follow-up
Vafaeimanesh et al[5]	39	Female	Dexamethasone (unknown dose)	Long time	Drowsiness, severe fatigue	Slight decrease in total calcium	Significantly increased ALT (2339 U/L; normal range: 7-41 U/L) and AST (2002 U/L; normal range: 12-38 U/L)	Cortisol: 2.5 μg/dL; ACTH: 11 (9-52) μg/dL	3 days	Prednisone therapy for 12 days	Liver function normalized, and the patient was discharged in good health
Present case	42	Male	Prednisone 30 mg/day initially, gradually tapered to 5 mg/day	Approximately 2 years	Fatigue, decreased appetite, abdominal distention, sweats	No	Slightly increased ALT (125 U/L; normal range: 9-50 U/L) and AST (80 U/L; normal range: 9-50 U/L)	Cortisol: 5.49 (8.7-22) μg/dL; ACTH: 25.41 (7.5-58) μg/dL	10 days	Intravenous compound diisopropylamine dichloroacctate and compound glycyrrhizin for 1 week	Fully recovered from both hospitalizations and is still healthy as of this writing

ACTH: Adrenocorticotropic hormone; AST: Aspartate aminotransferase; ALT: Alanine aminotransferase.

An unusual feature of the case presented here is that the patient lacked some typical symptoms of patients with hypertransaminasemia due to primary Addison's disease. Patients with hypertransaminasemia due to primary Addison's disease often present with fatigue, weight loss, gastrointestinal symptoms, skin hyperpigmentation, and hypotension despite several exceptional cases with no symptoms at all[10]. In contrast, some typical symptoms of Addison's disease, such as skin hyperpigmentation and hypotension, are absent in cases with hypertransaminasemia secondary to adrenal insufficiency caused by glucocorticoid withdrawal[5] due to a chronic course and possibly the side effects associated with glucocorticoid therapy[9].

Hypertransaminasemia due to Addison's disease has a slight sex predisposition favoring males and is more likely to affect young adults in previous reports[10]. Nevertheless, hypertransaminasemia secondary to Addison's disease can be discovered in all age groups from infants[11], due to congenital glucocorticoid deficiency or adrenocorticotropin deficiency, to the elderly[12], especially when considering that glucocorticoids may be used in patients of any age group. Interestingly, cholestasis is seen mainly in infants with adrenal insufficiency, while hypertransaminasemia is the major hepatic manifestation in other age groups, though co-existence of cholestasis and hypertransaminasemia can occur in any age[10,11].

The most remarkable feature of our case is that long-term follow-up showed that the severity of adrenal insufficiency may be associated with the development of elevated transminases. In the vast majority of previously reported cases of liver injury caused by adrenal insufficiency, slightly elevated hepatic enzymes are the most common feature; however, there has been a report of acute liver failure with a severe increase of liver enzymes (> 50 × upper limit of normal) secondary to adrenal insufficiency after discontinuation of long-term therapy with dexamethasone[5]. An elegant review by Kalambokis and Milionis[10], which comprehensively summarized the association between hypertransaminasemia and Addison's disease, has suggested that more severe adrenal insufficiency may be associated with higher levels of transminases, as supported by the evidence that patients with an Addisonian crisis tend to have significantly higher transminase levels. Our patient presented elevated transminases due to adrenal insufficiency following the initial withdrawal of long-term prednisone therapy; however, he did not develop hepatic dysfunction after withdrawal of a short-term glucocorticoid therapy approximately 2 years later despite the presence of symptoms reminiscent of glucocorticoid withdrawal syndrome. The difference in the duration of glucocorticoid therapy between the two occasions, which could have resulted in different degrees of hypothalamic-pituitary-adrenal axis suppression, might explain this discrepancy, lending support to the association of elevated transminase levels with the severity of adrenal insufficiency. In agreement with this hypothesis, the cases presented by Vafaeimanesh et al[5] and Li et al[8] had higher transminase levels and a more severe disease than our patient’s due to the fact that their patients discontinued the therapy with glucocorticoids at higher doses, which might have probably resulted in more severe adrenal insufficiency (Table 1).

In previously reported cases of hypertransaminasemia due to Addison's disease, it often took several months to make a final diagnosis of Addison's disease from the onset of symptoms[10]. In contrast, a diagnosis of hypertransaminasemia due to adrenal insufficiency caused by glucocorticoid withdrawal can be achieved in several days after the detection of hepatic enzyme abnormalities due to the history of glucocorticoid withdrawal prior to the presence of hypertransaminasemia, as in the case presented here and that reported by Vafaeimanesh et al[5]. However, in the case reported by Li et al[8], a clear diagnosis of iatrogenic adrenal insufficiency was inadvertently made only after a remarkable improvement in symptoms was noted following the use of dexamethasone to manage a fever suspected of being caused by a transfusion reaction, highlighting the importance of taking a complete history and raising the awareness of this rare condition among physicians, especially gastroenterologists or hepatologists whom such patients may first visit or be referred to. Since glucocorticoids are often used in conditions where hypertransaminasemia may be caused by the disease itself or other medications used simultaneously, the prevalence of this condition may be underestimated and the etiology of hepatic enzyme abnormalities is easily ignored by clinicians who are unaware of this rare condition[13].

Adrenal insufficiency is common in patients with liver disease, and this has led to the proposal of the term “hepatoadrenal syndrome”; however, liver injury is uncommon in patients with Addison's disease[5]. At present, it remains unclear why liver injury occurs in Addison's disease. Chronic hypo-perfusion[14], an immunologic reaction within hepatic tissue[15], and hepatocyte apoptosis and necrosis induced by cytokines locally released by infiltrating lymphocytes[16] have been proposed as the possible underlying mechanisms[3]. Liver biopsy performed in several cases have shown lymphocytic infiltrates in the portal or periportal zones, which may be a feature of autoimmune hepatitis[12,15]. Both Addison's disease and autoimmune thyroid disease may be a component of autoimmune polyglandular syndrome (also known as autoimmune polyendocrine syndrome) that is possibly associated with autoimmune hepatitis and hypertransaminasemia[10]. Intriguingly, our patient had a history of Grave’s disease, an autoimmune disorder that can cause hyperthyroidism. Whether such autoimmune diseases contribute to hypertransaminasemia due to adrenal insufficiency remains to be explored. The possible mechanisms linking adrenal insufficiency and liver injury have been systematically summarized in a previous review[10].

Despite alternative therapy such as continuous subcutaneous hydrocortisone infusion, oral glucocorticoid replacement therapy remains the cornerstone treatment for adrenocortical insufficiency[17]. Nearly all reported cases of hypertransaminasemia due to Addison's disease were treated with low-dose steroid replacement therapy and achieved a complete resolution of hypertransaminasemia[10]. Treatment with glycyrrhizin is another feature of our case. Glycyrrhizin, though not officially indicated for treating Addison's disease, can significantly reduce ALT and AST and improve liver function by inhibiting oxidative stress[18] and is widely used to treat hepatic diseases in China. On the other hand, several previous studies[19,20] have suggested that glycyrrhizin is able to increase cortisol availability and potentiate glucocorticoid action in patients with Addison's disease. Glycyrrhizic acid, a component of glycyrrhizin, can inhibit 11beta-hydroxysteroid dehydrogenase-2, an enzyme that inactivates cortisol to cortisone, and thus has a potential to increase serum cortisol[21]. Since our patient intended to discontinue the long-term glucocorticoid therapy for suspected pulmonary sarcoidosis according to his pulmonologist’s order and his prednisone dose had been tapered to a relatively low level at 5 mg/day before the discontinuation, which might have led to an adrenal insufficiency that was not so severe, he was only given glycyrrhizin and another liver-protecting drug (compound diisopropylamine dichloroacctate), and his ALT and AST returned to normal approximately 1 week later. In contrast, the case reported by Li et al[8], which had a long disease course and poor overall condition, had no good response to glycyrrhizin prior to the hormonal replacement therapy. Therefore, glycyrrhizin may only be an option for patients with mild adrenal insufficiency due to glucocorticoid withdrawal who have planned to discontinue this hormonal therapy with many side effects.

All reported patients with hypertransaminasemia due to Addison's disease had a good prognosis following hormonal replacement therapy[10]. However, this does not mean that timely recognition and treatment are not so important. There have been several reported cases of hypertransaminasemia with an Addisonian crisis, a potentially life-threatening condition[10,14]. The case reported by Vafaeimanesh et al[5] developed acute liver failure 3 days after discontinuation of long-term dexamethasone. Fang and Yu[7] reported a case of primary adrenal hypofunction manifesting as repeated shock and acute liver and kidney injury. In addition, death may occur in patients following abrupt cessation of glucocorticoid therapy[10]. Therefore, it is of great necessity to educate patients and clinicians about such risk and avoid improper discontinuation of glucocorticoid therapy. Currently, most recommendations on glucocorticoid tapering are disease-specific, and there is still debate over the optimal rate of tapering. Despite that, the tapering can follow three general stages: An initial rapid taper (glucocorticoid dose is higher than prednisone 10 mg or equivalent), gradual tapering (≤ 10 mg but > 5 mg), and slow tapering (≤ 5 mg). If possible, glucocorticoid tapering can be based on monitoring hypothalamic-pituitary-adrenal axis recovery by testing serum cortisol. Specific recommendations can be found in a recent review article[22].

CONCLUSION

We have documented a rare case of mild hypertransaminasemia occurring following withdrawal of long-term prednisone therapy, a potentially underestimated and easily ignored condition that may have different features from hypertransaminasemia due to primary Addison's disease and whose severity may be associated with the severity of adrenal insufficiency. Education of clinicians and patients to avoid improper discontinuation of glucocorticoid therapy, complete history taking for prompt recognition, and timely treatment are of great importance to prevent life-threatening events, such as acute liver failure and death. Glycyrrhizin may be an option for patients with mild adrenal insufficiency due to glucocorticoid withdrawal who have planned to discontinue this hormonal therapy.