Dysarthria and Weakness in a Patient with Cirrhosis

INTRODUCTION

Wilson’s disease is a rare autosomal recessive disorder of copper metabolism that often presents as liver disease with neuropsychiatric symptoms.¹ It is caused by a mutation in the ATP7B gene, which encodes the ATPase2 protein that is responsible for biliary excretion of copper, leading to copper accumulation in several organs including hepatocytes and basal ganglia of the brain.¹ Clinical presentation is highly variable and often mimics other diseases such as alcoholic liver disease with hepatic encephalopathy, leading to delays or misdiagnoses.¹ We report a case of a patient with a history of alcohol use and cirrhosis who presented with generalized weakness, dysarthria, insomnia, and depression. His cirrhosis was initially attributed to alcohol use, but the progressive neuropsychiatric symptoms led to the diagnosis of Wilson’s disease. The diagnostic conundrum may be further complicated in the setting of language barriers and healthcare literacy in underserved populations.

CASE DESCRIPTION

A 39-year-old man with presumed alcoholic liver disease presented to our primary care clinic with five months of generalized weakness. The weakness was diffuse, preventing him from raising his arms above his head and getting out of bed without support. He also developed diffuse muscle and joint pain, slurred speech, and resting hand tremors, all worsened at night. The progressive neurologic symptoms led to inability to perform his job in construction, anxiety, insomnia, and depression.

His past medical history was notable for a recent diagnosis of cirrhosis and portal hypertension made four months ago after he presented to the emergency department (ED) for easy gum bleeding and was found to have thrombocytopenia. At that time, minimal workup was initiated, as his cirrhosis was presumed due to his history of alcohol use. He drank 6–18 beers on weekends for over three years but quit two years ago. He was not prescribed any medication at this visit and was referred to outpatient gastroenterology for further work up.

Family history was never documented in the chart until this clinic visit noting that his three siblings passed away in their 20 s from liver disease. One sister might have had hepatitis B; however, the causes of liver disease in the others were unknown. In his social history, he recently immigrated from Honduras and had a difficult time navigating the healthcare system.

On physical examination, the patient appeared fatigued and anxious. Vital signs were 98°F, 80 beats per minute, 130/70 mmHg, and SpO₂ 98% on room air. Head, eyes, and oral exams showed congenital strabismus with left eye lateral deviation, dark colored eyes with no documented Kayser Fleischer rings, anicteric sclera, poor dentition, and gingivitis without active gum bleeding. Pulmonary and cardiovascular exams were normal. The abdominal exam was normal without ascites and hepatosplenomegaly. His joints were not swollen or tender. He was alert and oriented. His speech was harsh with posterior throat sounds and poor articulation. Cranial nerves were intact except for the finding of left congenital exotropia. The motor strength was 5/5 with normal tone, intact sensation, and normal reflexes. He was able to perform finger to nose and heel to shin at a slow pace. His gait was normal. The patient had resting hand tremors without cogwheel rigidity. There was no asterixis. Throughout the visit, the audio video Spanish interpreter had difficulty understanding the patient due to his raspy speech and colloquial Honduran slang. The patient was frustrated not knowing why he was weak.

Laboratory results revealed WBC 6.1 × 10³/uL (normal 4.5–12 × 10³/uL) with a normal differential, Hgb 14 g/dL (normal 14–18 g/dL), PLT 84 × 10³/uL (normal 150–400 × 10³/uL), AST 65 U/L (normal 13–39 U/L), alkaline phosphatase 207 U/L (normal 34–104 U/L), PT 18 s (normal 11.7–14.5 s), total protein 6.4 g/dL (normal 6–8.3 g/dL), and albumin 2.8 g/dL (normal 4.2–5.5 g/dL). ALT, GGT, ferritin, and iron panel were within normal limits. The total bilirubin was 1.1 mg/dL (normal 0.2–1.2 mg/dL) and direct bilirubin was 0.3 (normal 0.0–0.2 mg/dL). Additional studies included negative hepatitis panels, antinuclear antibodies, and anti-mitochondrial antibodies.

Abdominal ultrasound revealed coarse hepatic echotexture and nodular contour consistent with cirrhosis with an indeterminate 1.1 cm hyperechoic mass in the right hepatic lobe. Magnetic resonance imaging (MRI) abdomen showed cirrhotic liver morphology with innumerable regenerative nodules and stigmata of portal hypertension, as well as a liver lesion classified as a Liver Imaging Reporting and Data System (LI-RADS)- 4 with radiographic features concerning for “probable hepatocellular carcinoma” (Fig. 1). The LI-RADS defines the imaging findings suggestive of hepatocellular carcinoma (HCC) from 1 being definitely benign to 5 definitely HCC. To evaluate his dysarthria, an MRI of the brain displayed mild parenchymal volume loss.

Figure 1.

A 0.9 cm T2 hyperintense observation in hepatic segment 5/8. (LIRADS- 4 lesion, probable hepatocellular carcinoma).

Based on the constellation of progressive neuropsychiatric findings in the absence of features of hepatic encephalopathy, additional tests were performed to identify a potential unifying etiology. The laboratory data came back with a ceruloplasmin level of < 6 mg/dL (normal 18–58 mg/dL), serum copper level of < 23 ug/dL (normal 69–132 ug/dL), 24-h urine copper of 1148 ug (normal 3–35 ug/24 h), and copper/creatinine ratio > 1177 ug/g (normal 0–49 ug/g creatinine). A detailed ophthalmologic exam showed Keyser Fleischer rings on slit lamp exam. In the workup for the probable HCC, alpha fetoprotein (AFP) was 8.1 ng/mL (normal < 9 ng/mL), and the liver lesion biopsy displayed chronic portal inflammation and mild to moderate interface hepatitis without evidence of HCC (Fig. 2). The hepatic copper concentration by weight was 694.1 ug/g (normal 15–55 ug/g). Genetic testing indicated two ATP7B gene abnormalities, one “pathogenic” and one “likely pathogenic.” Since the “likely pathogenic” gene indicates over a 90% likelihood of pathogenicity, the diagnosis of Wilson’s disease was confirmed, and the patient was started on trientine.

Figure 2.

(A-D) Liver showing moderate portal inflammation (black arrows), mainly lymphocytes with some eosinophils (pink arrow) and plasma cells as well as ductular reaction (red arrow). There is mild to moderate interface hepatitis (blue arrow). (E)Trichrome did not show significant fibrosis. (F) PASD is negative for Alfa-1 antitrypsin globules. A&B. 100 × H&E stained​. C H&E 200 × magnification​. D. H&E 400 × magnification​. E: Trichrome special stain​. F: PAS special stain.

Repeat abdominal MRI two months later downgraded his LI-RADS- 4 lesion to a LI-RADS- 3, indicating intermediate probability of malignancy (Fig. 3). The gastroenterologist recommended repeat abdominal imaging and AFP level every 6 months for HCC surveillance. However, the patient became more anxious and overwhelmed with all the medical testing. Despite extensive discussion with the patient and his wife, he did not appear to understand the importance of treatment and decided to go back to Honduras.

Figure 3.

A 0.9 cm T2 hyperintense, T1 isointense observation in hepatic segment 5/8. (LIRADs- 3 lesion, intermediate probability of hepatocellular carcinoma).

DISCUSSION

Wilson’s disease can mimic many common hepatic, neurologic, and psychiatric conditions due to its myriad presentation of symptoms, causing a delay in diagnosis. The patterns with liver dysfunction and histology seen in Wilson’s disease can range from acute liver failure without cirrhosis to asymptomatic hepatic dysfunction with compensated cirrhosis. ^2–4

The neurologic manifestations of Wilson’s disease can be extremely diverse. For instance, the excess copper deposit in the liver can lead to hepatic encephalopathy which presents with cognitive impairment, hyperreflexia, and sleep disturbances.^5–7 However, Wilson’s disease can be distinguished from hepatic encephalopathy if symptoms fail to respond to ammonia-clearing agents, as clearance of copper metabolites is required to improve neurologic symptoms.⁸ Similarly, excess copper can also deposit into the basal ganglia, causing tremors, dystonia, dysarthria, dysphagia and other neurologic signs seen in movement disorders such as Huntington’s and Parkinson’s disease.⁵ Wilson’s disease can be differentiated from these movement disorders by symptom chronology, as liver dysfunction would precede neurologic signs and dysarthria tends to present earlier in Wilson’s disease than in other movement disorders.^5,9 Tremors, anxiety, and cognitive impairment seen in Wilson’s disease could be misattributed to sleep disturbances in patients with insomnia or underlying psychiatric disorders. Furthermore, the effects of neurotoxins such as alcohol on the brain and liver can present with similar clinical manifestations such as ataxia, dysarthria, depression, sleep disorders, and tremors.¹⁰

Moreover, Wilson’s disease is classically characterized by hepatic and extrapyramidal movement disorder with Parkinson's features and dystonia, yet dysarthria is the most common clinical presentation, occurring in up to 95% of Wilson’s disease patients with neurologic manifestation.⁵ Speech abnormalities are the first neurologic symptom in 46% of patients and can vary based on the brain lesion involvement. Dysarthria in Wilson’s disease can be categorized as 1) ataxic (cerebellar) with reduced coordination, irregular rhythm, and articulatory breakdown; 2) dystonic (hyperkinetic) with slurred speech and involuntary movements involving the facial muscles; 3) hypokinetic (parkinsonian-basal ganglia) with difficulty with initiation, quiet and slowed speech; 4) spastic (pseudobulbar, upper motor neurons) and slowed speech with monotone, mono-pitch, and distorted vowels; and 5) mixed which can entail the spectrum of components.^11,12

Acute Wilson’s disease with fulminant liver failure is typically associated with a low alkaline phosphatase, but this low level is less commonly seen in chronic forms.¹³ Therefore, an elevated alkaline phosphatase level does not exclude Wilson’s disease, as demonstrated in our patient. These variations in phenotype highlight the importance of considering Wilson’s disease in the differentials in patients with liver disease and neuropsychiatric features. The Leipzig scoring test can be used to establish a diagnosis of Wilson’s disease. The score is based on several criteria including neurologic symptoms, low serum ceruloplasmin, Coombs-negative hemolytic anemia, elevated liver copper and urinary copper in the absence of cholestasis, and mutation analysis of ATP7B gene.⁶ A score of 4 or more confirms the diagnosis.⁶ Our patient’s score was 14 based on his neurological symptoms, low serum ceruloplasmin levels, elevated liver and urinary copper levels, and genetic test result.

Wilson’s disease can be treated with copper-chelating agents (D-penicillamine and trientine) and zinc salts.¹⁴ Treatment delay in Wilson’s disease can cause progression of liver and neurologic deficits, ensuing death.¹² Prognosis is favorable when treated promptly, and liver function tests and neurologic deficits should improve within several months of initiating treatment.^12,13

A rare but known complication of Wilson’s disease is hepatocellular carcinoma (HCC).¹⁵ The cause of HCC in Wilson’s disease is believed to be due to oxidative injury and hepatocyte apoptosis seen with copper accumulation.¹⁵ However, the overall risk of HCC in Wilson’s disease is low, even in patients with cirrhosis; regular surveillance is not routinely recommended.¹⁵

Since Wilson’s disease is a treatable genetic disorder, obtaining a detailed family history is extremely important. In our case, failure to obtain a family history during the patient’s initial ED visit might have contributed to delay in diagnosis and care. Furthermore, the relevant family history is crucial especially when early genetic testing is recommended for asymptomatic patients with a 1^st degree family member with Wilson’s disease, as treatment can be started before symptom onset.¹⁶

The delayed diagnosis and medical care can often occur in underserved populations due to disparities in healthcare access, language barriers, education levels, and medical literacy. Published data has shown that patients with language barriers are less likely to seek healthcare and are more likely to miss appointments due to the fear of being misunderstood.¹⁷ The availability and utilization of in-person interpreters may alleviate these challenges, leading to improved treatment compliance.¹⁸ Lower education levels can contribute to lower health literacy, as standard patient education materials are often written above 6th grade reading levels.¹⁹ Clinicians should apply a “teach back” method by having patients describe their illness and treatment regimen to ensure patient understanding. In our case, the dysarthria and regional language dialect were the barriers to communication, and therefore, his wife was often included in the medical decision making. However, the patient’s healthcare anxiety and low health literacy remained challenges to overcome.

CONCLUSION

Wilson’s disease is a rare autosomal recessive disease that causes liver, neurologic, and psychiatric dysfunction. The onset of the disease is quite heterogeneous, and patients may present with dysarthria and generalized weakness, mimicking other common disorders such as liver and neurological diseases due to alcohol use. Our case highlights the ramifications of delayed diagnosis in a patient with a rare but treatable disease. In underserved populations, the effects of healthcare anxiety, medical literacy, and language barriers can all delay diagnosis causing further disparity. Wilson’s disease must be on the differential diagnosis in patients with liver disease and neuropsychiatric symptoms, as early identification and treatment can reverse the dysfunctions and avoid adverse outcomes.

Declarations:

Conflicts of Interest:

None.