Acquired hepatocerebral degeneration (AHD) is a neurological condition resulting from the accumulation of toxic cerebral metabolites, mainly manganese (Mn), through a portosystemic shunt (PSS) that circumvents hepatic metabolism (1). AHD is diagnosed based on the presence of a PSS, bilateral a hyperintense globus pallidus on T1-weighted brain magnetic resonance imaging (MRI), and neurological symptoms. The diagnosis of typical cases of AHD is not difficult because it occurs concomitantly with advanced liver disease, such as cirrhosis. However, diagnosis becomes challenging when AHD is caused by a PSS without underlying liver disease. One possible cause of such a shunt is a congenital malformation, namely congenital PSSs (CPSS) (2). Prior reports have only focused on hepatic encephalopathy associated with CPSS and have not detailed AHD due to this malformation (3).

The core pathophysiology of AHD has been linked to manganese-related neurotoxicity in the basal ganglia, leading to motor dysfunction, including parkinsonism, and cognitive impairments (4). Mn-related neurotoxicity can cause psychiatric symptoms, classically referred to as “manganese madness,” as observed in occupational manganism resulting from Mn exposure (1). “Manganese madness” is characterized by various psychiatric symptoms, including emotional lability, mood swings, attention deficits, impulsive and compulsive behavior, sleep disturbances, and hallucinations. Mn-related neurotoxicity is mediated through multiple mechanisms, such as inflammation and oxidative stress, leading to the proposed primary pathophysiology: dysfunction of dopaminergic neurons (5). A recent study found that exposure to low Mn doses, even in nonoccupational settings, can cause psychiatric manifestations, particularly depression (6). Despite the considerable potential of Mn-induced neurotoxicity to elicit psychiatric symptoms, few reports have addressed this psychiatric aspect of AHD. This may be partly because psychiatric symptoms of AHD can be conflated with hepatic encephalopathy associated with hyperammonemia (7).

Essential therapeutic strategies for AHD involve mitigating Mn accumulation. Liver transplantation is the most effective treatment for AHD in cases complicated by liver disease (7). Shunt embolization has emerged as a potential strategy for alleviating Mn accumulation by addressing hepatic clearance failure due to PSSs (8), irrespective of the presence or absence of liver disease. To the best of our knowledge, no prior studies have demonstrated the efficacy of shunt embolization in treating unique psychiatric symptoms of AHD.

This is the first report to describe the psychiatric symptoms of a patient with AHD due to CPSS that cannot be explained by the effects of hepatic encephalopathy. It is also the first to demonstrate the efficacy of shunt embolization for various symptoms of AHD, including psychiatric symptoms. The authors conveyed the significance of this study to the patient and her husband through written and verbal communication and secured their written consent.

To the best of our knowledge, this case study is the first to detail the psychiatric symptoms of AHD due to CPSS, without hepatic encephalopathy complications. Furthermore, it documents the efficacy of shunt embolization in sustaining the remission of psychiatric manifestations of AHD due to CPSS. The study also highlights a diagnostic challenge in AHD, particularly in the absence of liver disease, when psychiatric symptoms manifest as the initial clinical presentation.

Psychiatric symptoms associated with PSSs are commonly associated with hepatic encephalopathy but infrequently to AHD. This understanding may stem from the difference between hepatic encephalopathy, which has a high prevalence and distinctive characteristics, such as acute onset altered consciousness and hyperammonemia, and AHD, which has a comparably lower prevalence and manifests with a chronic onset and nonspecific symptoms (7). Moreover, the psychiatric manifestations of AHD may have been previously underestimated because of the co-occurrence of hepatic encephalopathy in the same patient (3). While hepatic encephalopathy and AHD are often discussed as distinct complications of chronic liver disease, some researchers propose that they form part of a single disease continuum, united by a chronic neuroinflammatory process driven by the accumulation of several toxic substances due to hepatic clearance failure (7). This common disease spectrum is also often referred to hepatic encephalopathy, which might have contributed to the less established recognition of psychiatric symptoms associated with AHD. In this study, hepatic encephalopathy is described specifically as a pathological condition characterized by hyperammonemia and acute encephalopathy, primarily involving disturbances in consciousness.

In the present case study, despite the absence of overt disturbances in consciousness, as confirmed by repeated electroencephalography showing normal baseline activity, neurological and psychiatric symptoms persisted. Supported by consistently normal blood ammonia levels, these findings prompted the exclusion of hepatic encephalopathy. A previous case series of AHD with liver disease reported that psychiatric symptoms were observed in 33% of 15 patients with AHD in the absence of hyperammonemia, demonstrating that psychiatric manifestations in AHD are not uncommon (9). Notably, one patient (6.7%) initially manifested psychiatric symptoms solely. These findings confirm that AHD is sometimes difficult to differentiate from psychiatric disorders.

Consistent with observations in the previous case series (9), the present case study reported various psychiatric symptoms, ranging from mild anxiety to catatonia, with major depression emerging as the predominant manifestation. These symptoms are similar to those observed in occupational manganism, which is characterized by the common pathophysiology of Mn neurotoxicity. Despite the absence of elevated blood Mn concentration in the present case, the existing literature indicates that blood Mn concentration is not a reliable indicator of Mn body burden and does not reflect the MRI signal or neurological sequelae of AHD (10). In addition, shunt embolization not only prevented relapse in motor and psychiatric symptoms but also significantly alleviated abnormal brain MRI findings indicative of cerebral Mn accumulation. Therefore, we contend that our case represents a clinical syndrome resulting from Mn-related neurotoxicity. Substantial evidence shows that a pathophysiological mechanism in Mn-induced neurotoxicity is linked to dopamine dysfunction (11), which can induce parkinsonism, psychiatric symptoms, and pain (12, 13).

CPSS, which has an incidence rate of 1 in 30,000, can manifest its initial complications in adulthood, as evidenced by one-third of cases being diagnosed after the age of 12 years, and of some instances reported even beyond the age of 80 years (2). CPSSs are classified according to the presence or absence of an intrahepatic portal vein and the shunt location; type 1 denotes the absence of the intrahepatic portal vein, whereas type 2 indicates its presence (2). The present case was classified as extrahepatic type 2 CPSS. This type of CPSS, where a shunt vessel linking the left gastric vein to the left renal vein converges with the portal vein, is rare. These anatomic features will have restricted the occurrence of complications from CPSS, delaying the diagnosis until middle age. Due to the rare characteristics of this case, the diagnosis of AHD was established 5 years after the identification of distinct MRI features. This case study highlights the importance of considering AHD in adult-onset psychiatric disorders, such as depression, when T1-weighted MRI shows high-signal findings in the globus pallidus, irrespective of the presence of liver disease or elevated blood Mn concentrations.

This case study has several limitations. First, the relationship between the severity of CPSS and the risk of developing complications, particularly the factors causing AHD to manifest after middle age in this case, remains unclear. Second, because of the relatively brief observation period of approximately 3 years after shunt embolization, the assessment of the long-term risk of relapse and impact of shunt embolization on cognitive dysfunction may be premature. Finally, a significant limitation in this case is the inability to rule out the potential involvement of cerebral toxic metabolites, evading hepatic metabolism, other than Mn, in the pathophysiology.

Overall, this case emphasizes the importance of a heightened awareness of AHD due to CPSS in the fields of neurology and psychiatry, especially with hyperintensity in the globus pallidus on T1-weighted MRI. Furthermore, this study has identified the potential of shunt embolization as a highly effective treatment for AHD due to CPSS.

The original contributions presented in the study are included in the article/supplementary material. Further inquiries can be directed to the corresponding author.

The Ethics Review Committee of the Faculty of Medicine at Tokyo Medical and Dental University stated that ethical review is not required for case reports when individual consent is obtained, and therefore, ethical review was waived for this case study. The studies were conducted in accordance with the local legislation and institutional requirements. The participants provided their written informed consent to participate in this study. Written informed consent was obtained from the participant for the publication of any potentially identifiable images or data included in this article.

TT: Conceptualization, Data curation, Funding acquisition, Investigation, Project administration, Resources, Supervision, Visualization, Writing – original draft, Writing – review & editing. ST: Investigation, Resources, Supervision, Writing – original draft, Writing – review & editing. AH: Investigation, Resources, Writing – review & editing. JO: Investigation, Methodology, Resources, Supervision, Visualization, Writing – review & editing. JF: Investigation, Resources, Supervision, Writing – review & editing. HS: Investigation, Resources, Supervision, Writing – review & editing. HT: Investigation, Resources, Supervision, Writing – review & editing. GS: Conceptualization, Investigation, Resources, Supervision, Writing – original draft, Writing – review & editing.