Steatotic liver disease arising in an asymptomatic 20-year-old man with panhypopituitarism and elevated transaminases
Abstract
Background:
Steatotic liver disease (SLD) may be caused by cardiometabolic risk factors, drugs/toxins, viral hepatitis, genetic diseases, malnutrition, or panhypopituitarism. SLD can advance to steatohepatitis with resulting lipid accumulation, inflammation, and hepatocellular damage. SLD is associated with pituitary dysfunction, in particular growth hormone deficiency, as insulin resistance leads to lipid buildup and oxidative stress. Growth hormone replacement may improve liver steatosis and fibrosis in patients with hypopituitarism.
Case:
We report a case of a 20-year-old man who was referred to Hepatology with abnormal liver enzymes. He had panhypopituitarism from a resected pituitary mass, for which he was treated with levothyroxine, hydrocortisone, growth hormone, and testosterone. He presented with elevated liver enzymes, normal liver function, obesity, dyslipidemia, and had no extrahepatic manifestations of chronic liver disease. Work-up for secondary causes of liver disease, including infectious, autoimmune, drug-induced, and genetic causes, were negative. An abdominal ultrasound revealed moderate hepatic steatosis with mild hepatomegaly and splenomegaly. His liver enzymes remained elevated, and his biochemical liver function remained normal despite withdrawal of hepatotoxic medications. Liver biopsy showed grade II/III steatohepatitis with stage III-IV fibrosis. The biopsy results suggested that panhypopituitarism, with growth hormone deficiency and related metabolic dysfunction, caused his liver disease.
Conclusions:
This is a unique case of an aggressive form of SLD due to panhypopituitarism, and treating growth hormone deficiency with hormone replacement did not improve liver enzymes or liver damage. Physicians should recognize SLD as a serious complication of panhypopituitarism and resulting growth hormone deficiency and follow patients closely given the risk of disease progression.
Lay Summary: Fatty liver disease, also known as steatotic liver disease, can develop as a result of metabolic factors, such as body weight and high blood sugar. After significant fat buildup occurs in liver cells, steatotic liver disease can progress to a condition called steatohepatitis with widespread liver inflammation and cell damage. A disorder in the pituitary gland can cause abnormalities in hormone signaling pathways, such as growth hormone, and has been found to lead to steatotic liver disease. One of the possible mechanisms for this association is that insulin resistance may cause further accumulation of fat and cell damage due to oxidative stress. Patients with a malfunctioning pituitary gland and growth hormone deficiency have shown improvements in liver damage after treatment with growth hormone replacement. Here, we report a case of a 20-year-old man who was referred to the Hepatology Clinic with abnormal liver enzymes. He previously had a pituitary mass removed, so he was treated with thyroid, steroid, growth, and sex hormone replacement. He presented with elevated liver enzymes, normal liver function, elevated cholesterol, obesity, and no findings of liver disease on physical examination. Investigations into causes of liver disease, including infectious, autoimmune, drug-induced, and genetic cause, were negative. An abdominal ultrasound showed liver inflammation and enlargement. Liver-toxic medications were withdrawn but laboratory findings remained the same. A liver biopsy showed inflammation and scarring of the liver tissue and determined that due to his inadequate production of pituitary hormones, he developed growth hormone deficiency, metabolic dysfunction, and ultimately liver disease. The patient's case is unique, as he was found to have severe liver damage, and long-term treatment with growth hormone therapy did not lead to any improvement. Physicians should consider fatty liver disease as a complication of pituitary dysfunction and follow patients closely given the high likelihood of disease progression.
Introduction
Metabolic dysfunction-associated steatotic liver disease (MASLD) is a leading cause of steatotic liver disease (SLD) and a large contributor to liver-related morbidity and mortality (1,2). The presence of steatosis and the accumulation of lipids within hepatocytes is a defining characteristic of MASLD (3,4). Several cardiometabolic risk factors, including obesity, diabetes mellitus, and insulin resistance, can cause hepatic steatosis seen in MASLD (2,5,6). Other causes of SLD, including alcohol-associated liver disease, drug-induced liver injury, and rare genetic diseases, as well as miscellaneous causes, such as viral hepatitis, autoimmune hepatitis, endocrine disorders, malnutrition, and celiac disease, must be excluded in all patients (2,6,7). Non-alcohol drug toxicity has been linked to the development of steatosis and steatohepatitis in approximately 2% of SLD cases, with commonly implicated drugs, including aspirin, amiodarone, corticosteroids, methotrexate, valproic acid, and antiretrovirals (2).
SLD may progress to steatohepatitis, whereas steatosis is accompanied by inflammatory cells and hepatocellular damage (3,4). The development of steatohepatitis is believed to be related to insulin resistance, which causes fat accumulation in hepatocytes and increased mitochondrial reactive oxygen species that cause lipid peroxidation and inflammation (8,9). Evidence of hepatic steatosis and inflammation may be seen on liver imaging or on pathohistologic findings from liver biopsy and can aid in the diagnosis of liver disease (9). Steatohepatitis may advance to liver fibrosis, cirrhosis, hepatocellular carcinoma, liver failure, and may require for liver transplant (3).
The development of SLD has been reported to be associated with hypothalamic and pituitary dysfunction, in particular growth hormone deficiency (3,5,10,11). Growth hormone stimulates the production of insulin-like growth factor 1 (IGF-1) in the liver and exerts its physiologic effects through increasing lipolysis in adipose tissue, increasing beta-oxidation of free fatty acids, and downregulating de novo lipogenesis in hepatocytes (3,12,13). IGF-1 displays anti-inflammatory and anti-fibrotic properties in the liver (3). Individuals with hypopituitarism and resulting growth hormone deficiency may experience metabolic changes, such as central obesity, hyperlipidemia, and insulin resistance (8,11,14). Derangements in the growth hormone and IGF-1 pathway may contribute to the development of SLD and steatohepatitis by promoting lipid accumulation in hepatocytes, insulin resistance, and liver inflammation (1,4). There have been documented cases of patients with hypopituitarism who displayed rapid weight gain and developed hyperlipidemia, hyperglycemia, and SLD after the onset of hormonal dysfunction (2,14). Growth hormone replacement therapy has been shown to reverse abnormal liver enzymes and improve steatosis and fibrosis, highlighting its importance as a potential therapy in patients with SLD (2,11). The following case describes a 20-year-old man with panhypopituitarism who was found to have significantly elevated liver enzymes with steatohepatitis and fibrosis seen on liver biopsy.
Case
A 20-year-old man was referred to the hepatology clinic for assessment of abnormal liver enzymes. The patient had experienced headaches of increasing frequency and intensity for three years before diagnosis of a Rathke cleft cyst in his pituitary gland with associated pituitary dysfunction. Following transsphenoidal surgery in 2017, he started hormone replacement therapy with levothyroxine, hydrocortisone, somatropin (growth hormone), and gonadotropin alpha (testosterone). He was first seen by the neuropituitary specialist in May 2022, where his IGF-1 level was 339 ng/mL (normal range, 105–346 ng/mL) and testosterone level was 34.9 nmol/L (normal range, 8.0–32.0 nmol/L). The growth hormone medication was withdrawn as therapy was not indicated since he was post-pubertal. Subsequent IGF-1 measurements were low (80 ng/mL in July 2022 and 30 ng/mL in April 2024). He was also found to have elevated transaminase levels, so testosterone therapy was discontinued out of caution (Table 1). Of note, the patient reported liver enzyme abnormalities since 2017. However, we lacked access to these results because his care before 2022 was in a different country.
| Laboratory Test | Initial Result | Reference Range |
|---|---|---|
| Alanine Transaminase (µkat/L) | 9.23 | 0–0.9 |
| Aspartate Transaminase (µkat/L) | 4.28 | 0.08–0.75 |
| Alkaline Phosphatase (µkat/L) | 2.92 | 0.63–2.5 |
| Gamma-Glutamyl Transferase (µkat/L) | 6.05 | 0–0.82 |
| Total Bilirubin (μmol/L) | 15.9 | 0.0–20.4 |
| International Normalized Ratio | 1.0 | 0.8–1.2 |
| Albumin (g/L) | 50 | 35–50 |
| Platelets (×109/L) | 261 | 150–350 |
| Cholesterol (mmol/L) | 7.2 | – |
| Triglycerides (mmol/L) | 2.5 | <1.7 |
| Low-density Lipoprotein (mmol/L) | 4.8 | – |
At the time of initial assessment by a hepatologist in February 2023, he had normal liver function and had a normal physical examination with a BMI of 31 (Table 1). There were no extrahepatic manifestations of chronic liver disease or liver-related decompensation, such as ascites, hepatic encephalopathy, peripheral leg swelling, or varices. He had no family history of liver disease. Investigations into causes of chronic liver disease included elevated cholesterol markers (Table 1), normal immunoglobulins, negative hepatitis C antibody screen, non-reactive hepatitis B surface antigen, normal ceruloplasmin (264 mg/L), negative antinuclear antibody, normal glycated hemoglobin (5.4%), normal alpha-1-antitrypsin (28.15 µmol/L), negative anti–liver-kidney-microsomal antibody, negative antimitochondrial antibody, negative anti-smooth muscle antibody, and normal tissue transglutaminase immunoglobulin A (<0.5 U/mL). There was no history of alcohol, illicit drug, over-the-counter medication, or herbal supplement use. An abdominal ultrasound showed moderate hepatic steatosis with mild hepatomegaly and splenomegaly.
The patient's growth hormone and testosterone therapy continued to be ‘held’. However, his liver enzymes remained elevated over the next year (alanine transaminase level, 8.98 µkat/L; aspartate transaminase level,6.39 µkat/L; alkaline phosphatase level 2.47 µkat/L; gamma-glutamyl transferase level, 6.03 µkat/L), with liver function remaining normal. A percutaneous liver biopsy revealed grade 2 of 3 steatohepatitis and mild macrovesicular steatosis, in transition to cirrhosis with stage 3-4 of 4 fibrosis (Figure 1). The iron stain in the liver biopsy was negative. A FibroScan demonstrated a liver stiffness score of 21.8 kPa, which aligned with the biopsy result and indicated advanced chronic liver disease. The pathologic findings suggested causes of chronic liver disease, including metabolic dysfunction-associated steatohepatitis, drug-induced, or growth hormone deficiency, and ruled out other rare causes, including lysosomal acid lipase deficiency, Wilson disease, and hemochromatosis. Based on the severity of his biopsy findings, the patient's liver disease was presumed to be largely due to panhypopituitarism with resultant metabolic dysfunction and intermittent growth hormone deficiency.
The hepatologist continues to follow the patient with bloodwork every four months and abdominal imaging every six months. They have advised the neuropituitary clinic to treat the patient with hormone replacement therapy based on age-appropriate and clinical guidelines. He has been restarted on testosterone therapy, but he has not resumed growth hormone replacement due to insurance coverage. The patient continues to be free of clinical signs of liver disease, and his repeat abdominal ultrasound remains unchanged, despite persistently elevated liver enzymes.
Discussion
The prevalence of MASLD is known to be higher in patients with panhypopituitarism, and specifically growth hormone deficiency, with the underlying mechanisms consisting of the development of insulin resistance, accumulation of lipids in hepatocytes, and increased oxidative stress (9,14). The severity of SLD has been found to be inversely related to growth hormone levels (3). In our case, the patient had a history of panhypopituitarism of unknown duration due to a Rathke cleft cyst. His panhypopituitarism appeared corrected on hormone replacement, and he presented with a normal IGF-1 level. However, he rapidly developed growth hormone deficiency once replacement therapy was discontinued and this coincided with significant worsening of transaminitis. He was found to have biopsy-proven, moderately active, steatohepatitis and advanced fibrosis at only 20-years-old. This is suggestive that the severity of his liver disease had been driven by panhypopituitarism, specifically growth hormone deficiency, and compounded by metabolic dysfunction (obesity and dyslipidemia).
The initial step in ruling out causes of elevated transaminases and chronic liver disease in our patient was withdrawing medications known to have adverse effects on the liver. The patient's growth hormone and testosterone replacement medications were withdrawn, as they have been shown to cause transient increases in serum liver enzyme levels (15–17). Although, treatment with corticosteroids has been shown to cause steatohepatitis, it rarely causes progression to fibrosis or cirrhosis, making it less likely to be the cause of liver disease in our patient (2). Most notably, he is prescribed 15 mg of hydrocortisone a day, which is considered a daily physiologic dose in adults. Further investigation into the cause of the patient's SLD proved unrevealing. The marked alanine transaminase and aspartate transaminase elevation is uncharacteristic of most causes of chronic SLD and further suggests that panhypopituitarism with intermittent growth hormone deficiency may be driving his disease.
There has been documented normalization of serum transaminase levels in patients with growth hormone deficiency and steatohepatitis or in patients with obesity and MASLD who received growth hormone replacement for at least six months (5,9,12,18). However, our patient presented with elevated liver enzymes despite being on growth hormone replacement for approximately five years, but, interestingly, transaminitis significantly worsened after withdrawing growth hormone and testosterone replacement medications. Previous cases of growth hormone deficiency due to panhypopituitarism, with findings of steatohepatitis on biopsy, including inflammatory infiltrates and hepatocyte ballooning, have shown significant improvement in fatty changes of the liver and liver function with growth hormone replacement over a six-to-twelve-month time period (5,8–10). In our patient, despite five years of growth hormone replacement, his SLD may have developed immediately following the onset of impaired growth hormone signaling, which was of uncertain duration before diagnosis. Replacement therapy may have been insufficient to reverse the liver damage (1). This case suggests that panhypopituitarism can cause rapid progression of fibrosis, even in young individuals, likely due to the interplay with metabolic dysfunction and its association with obesity and diabetes mellitus, which has been previously highlighted in a few cases in the literature (11).
Our patient may require prolonged treatment with growth hormone in order to stabilize and prevent further progression of his liver disease. While the patient's weight remained stable throughout his work-up, obesity is a known risk factor for MASLD, and control of body weight during growth hormone treatment is necessary to obtain a positive effect (18). If and when the patient resumes growth hormone replacement, improvement or resolution of transaminitis, imaging findings, and histology would support our hypothesis that growth hormone deficiency is a major contributor to his liver disease.
In conclusion, this case report describes an unusual presentation of SLD with advanced fibrosis likely related to panhypopituitarism, growth hormone deficiency, and metabolic derangement. Based on his young age at both presentation and diagnosis of advanced chronic liver disease, it is imperative for physicians to recognize that panhypopituitarism may lead to a more aggressive form of SLD compared to other causes, which classically progress slowly before causing advanced fibrosis. There is sufficient evidence to support that treatment with growth hormone, even into adulthood, may decrease the likelihood of developing SLD by increasing IGF-1 levels, and by ultimately reducing hepatic steatosis, inflammation, and cell damage (1,11). Unfortunately, the cost of growth hormone therapy prohibits our patient from currently receiving treatment, potentially further worsening his liver fibrosis. In the future, the case patient, and other similar patient presentations, would benefit from receiving treatment and follow-up as part of a multidisciplinary team, with different physicians and allied health services, such as dietician, social work, and occupational therapy, given the degree of his multimorbidity, and to assist with enabling earlier recognition of liver involvement. Endocrinologists and hepatologists should screen for SLD in all patients with panhypopituitarism and growth hormone deficiency and arrange long-term follow-up, as disease may occur and progress even if on adequate hormone replacement.
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This manuscript was peer reviewed.
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Information & Authors
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Published In
Canadian Liver Journal
Volume 7 • Number 4 • December 2024
Pages: 511 - 516
Copyright
© Canadian Association for the Study of the Liver, 2024. This article is free to read to all interested readers, immediately upon publication. For their own personal use, users may read, download, print, search, or link to the full text. Manuscripts published in the Canadian Liver Journal are copyrighted to the Canadian Association for the Study of the Liver. Requests for permission to reproduce this article should be made to the University of Toronto Press using the Permission Request Form: https://canlivj.utpjournals.press/policies#_copyright or by email: [email protected].
History
Received: 25 July 2024
Revision received: 16 September 2024
Accepted: 23 September 2024
Published online: 19 December 2024
Published in print: December 2024
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Authors
Contributions:
Conceptualization, N Wiebe, A Stueck, M McLeod; Data curation, N Wiebe, A Stueck; Writing – Original Draft, N Wiebe, A Stueck; Writing – Review and Editing, N Wiebe, A Stueck, M McLeod.
Disclosures:
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Informed Consent:
We confirm that written informed consent was obtained from the patient for publication of this case report.
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Canadian Liver Journal 2024 7:4, 511-516
Canadian Liver Journal 2024 7:4, 511-516