Medical Case: What's behind mild liver test abnormalities?

Persistent mild biochemical abnormalities rarely trigger diagnostic escalation. This case highlights the hidden significance of subtle neurological and hepatic findings.

Case presentation

Marc L., a 29-year-old office worker, presented to his primary care physician with progressive fatigue, reduced concentration, and intermittent hand tremor. He reported that symptoms had developed gradually over several months and were increasingly affecting his work performance. He denied acute complaints, pain, or recent illness.

Marc lived with his partner and had no children. He described a largely sedentary lifestyle. He was a non-smoker and reported only occasional alcohol consumption, typically limited to social settings. He denied illicit drug use and was not taking regular medications.

Physical examination was largely unremarkable. Vital signs were within normal limits. Neurological assessment revealed a fine postural tremor but no focal deficits. No clinical signs of chronic liver disease were observed.

Past medical history

Marc’s prior history was notable for persistently abnormal liver biochemistry first documented three years earlier during occupational screening. At that time, he was asymptomatic.

Initial laboratory findings included:

Abdominal ultrasound demonstrated mild hepatic steatosis without fibrosis. No further evaluation was pursued. Serial follow-up confirmed stable but persistent aminotransferase elevation. Screening for viral, autoimmune, and iron-related liver diseases was unrevealing.

Recent clinical course

Over the year preceding presentation, the patient developed increasing fatigue and subtle behavioural changes, including irritability and decreased cognitive efficiency. Family members reported subtle changes in speech fluency, which the patient himself had not initially recognised.

Laboratory tests obtained approximately three weeks prior to the current evaluation demonstrated:

This constellation was suggestive of haemolysis in the context of persistent hepatocellular injury. Notably, the ALP/total bilirubin ratio was <4, a biochemical relationship that may provide an important diagnostic clue in selected metabolic conditions. Although Marc’s course was chronic, the disproportionate reduction of ALP relative to bilirubin was considered clinically significant.

Neurological assessment

Neurological evaluation performed approximately six weeks after the initial primary care consultation confirmed:

In retrospect, this contributed to diagnostic anchoring. In more advanced stages of certain metabolic or toxic disorders, MRI may demonstrate T2 signal abnormalities within the basal ganglia. The absence of early imaging changes may therefore delay diagnostic recognition.

Diagnostic reconsideration

During hepatology consultation, the coexistence of persistent hepatocellular enzyme abnormalities, subtle neurological findings, and laboratory features suggestive of haemolysis prompted renewed diagnostic evaluation. At this stage, the clinical picture lacked a unifying explanation within the framework of common hepatic or neurological disorders.

Repeat laboratory testing demonstrated:

The disproportionately low ALP value relative to bilirubin, together with biochemical evidence suggestive of haemolysis, represented an atypical pattern. While each abnormality was individually non-specific, their combination raised suspicion for an underlying metabolic disorder.

Targeted metabolic investigations were therefore obtained:

Although only modestly reduced, this finding was considered abnormal when interpreted in conjunction with the broader clinical and biochemical context.

At this stage, the diagnostic framework remained uncertain.

What would you diagnose?

Diagnostic outcome

Measurement of 24-hour urinary copper excretion revealed markedly elevated values. Subsequent slit-lamp examination demonstrated brownish-green corneal deposits at the level of Descemet’s membrane, consistent with Kayser–Fleischer rings. Genetic analysis confirmed pathogenic variants affecting copper transport. The constellation of findings established the diagnosis of Wilson disease with combined hepatic and neurological involvement.

The diagnostic framework was consistent with the Leipzig scoring system, integrating clinical features (Kayser–Fleischer rings, neurological signs), biochemical markers (reduced ceruloplasmin, elevated urinary copper), and genetic testing.

Where available, newer biomarkers of copper metabolism (such as exchangeable copper parameters) may further support diagnostic evaluation.

Clinical course and complications

At the time of diagnosis, neurological manifestations progressed rapidly, with worsening tremor, dysarthria, and gait instability. Hepatic involvement also evolved, as evidenced by declining synthetic function:

  • INR progressively rising from 1.2 to 1.8
  • Serum albumin: reduced

Episodes of haemolytic anaemia became more pronounced, reflecting systemic effects of copper toxicity.

Chelation therapy was initiated promptly following diagnosis. However, neurological recovery remained incomplete, consistent with observations that advanced neurological injury may be only partially reversible. Progressive hepatic dysfunction ultimately required referral for liver transplantation assessment.

Clinical reasoning and discussion

This case illustrates how persistent but mild liver test abnormalities may lead to diagnostic inertia, particularly when imaging findings such as steatosis appear to provide a plausible explanation. In young adults, metabolic-associated steatotic liver disease is increasingly prevalent, yet it must remain a diagnosis of exclusion.

The combination of neurological features, haemolytic indices, and disproportionately low alkaline phosphatase values represented critical diagnostic signals. Importantly, the reduction in ceruloplasmin was modest, highlighting the limited value of isolated testing strategies.

Delayed recognition permitted disease progression to partially irreversible neurological injury and advanced hepatic dysfunction despite the availability of effective disease-modifying therapy.

Take-home message

  1. Think Wilson: In young adults, persistent aminotransferase elevation without a clear explanation should always prompt consideration of Wilson disease — even when abnormalities are mild and the clinical picture appears reassuring.
  2. Look at ALP: Routine liver tests may conceal critical diagnostic clues. A disproportionately low alkaline phosphatase level relative to bilirubin, particularly when associated with haemolytic features, represents an important warning signal for disorders of copper metabolism.
  3. Beyond Steatosis: Hepatic steatosis is common, but in young patients it must remain a diagnosis of exclusion. The presence of fatty liver should not lead to diagnostic closure when clinical or biochemical inconsistencies suggest alternative or rarer conditions.
  4. Avoid diagnostic closure: Common diagnoses explain common findings, but rare diseases often hide behind them. Persistent discordance between clinical features and routine investigations should always justify renewed diagnostic curiosity.

Wilson disease in clinical practice

Wilson disease is a rare autosomal recessive disorder of copper metabolism caused by pathogenic variants in the ATP7B gene, resulting in impaired biliary copper excretion and progressive copper accumulation. The estimated prevalence is approximately 1 in 30.000 individuals, with a carrier frequency of roughly 1 in 90, although regional variability exists. Because of underrecognition and phenotypic heterogeneity, true prevalence may be higher than traditionally reported.

Clinical presentation typically occurs between the first and fourth decades of life, most commonly during adolescence or young adulthood. Hepatic manifestations often predominate in children and younger patients, whereas neurological and neuropsychiatric features are more frequently observed in adolescents and adults. However, age at diagnosis is highly variable, and delayed recognition remains common, particularly in patients with mild or non-specific early findings.

Diagnosis requires a composite assessment integrating biochemical markers (including ceruloplasmin and 24-hour urinary copper excretion), ophthalmological evaluation, and genetic testing. No single parameter is sufficient to exclude the disease. Early detection is essential, as timely initiation of copper-lowering therapy can prevent irreversible hepatic and neurological injury, whereas delayed diagnosis may result in progressive organ dysfunction and permanent neurological sequelae.

References
  1. European Association for the Study of the Liver. EASL-ERN Clinical Practice Guidelines on Wilson's disease. J Hepatol. 2025 Feb 22:S0168-8278(24)02706-5. doi: 10.1016/j.jhep.2024.11.007. Epub ahead of print. PMID: 40089450.
  2. Członkowska A, Litwin T, Dusek P, Ferenci P, Lutsenko S, Medici V, Rybakowski JK, Weiss KH, Schilsky ML. Wilson disease. Nat Rev Dis Primers. 2018 Sep 6;4(1):21. doi: 10.1038/s41572-018-0018-3. PMID: 30190489; PMCID: PMC6416051.
  3. Shribman S, Poujois A, Bandmann O, Czlonkowska A, Warner TT. Wilson's disease: update on pathogenesis, biomarkers and treatments. J Neurol Neurosurg Psychiatry. 2021 Oct;92(10):1053-1061. doi: 10.1136/jnnp-2021-326123. Epub 2021 Aug 2. PMID: 34341141.
  4. Orphanet. Wilson disease. Orphanet Rare Disease resource.