In a 76‑year‑old man with ketonuria and conjugated bilirubinuria, can the listed differential diagnoses cause progressive fatigue and loss of appetite?

Progressive Fatigue and Loss of Appetite in Cholestatic Liver Disease

Yes, all the major differential diagnoses for ketonuria and conjugated bilirubinuria—including primary biliary cholangitis (PBC), autoimmune hepatitis (AIH), and prerenal azotemia—commonly cause progressive fatigue and loss of appetite in a 76-year-old man.

Primary Biliary Cholangitis (PBC)

Fatigue is a cardinal symptom of PBC and should be specifically assessed during history and physical examination. 1

• The American Association for the Study of Liver Diseases explicitly recommends obtaining detailed history assessing for fatigue as a core diagnostic feature of PBC. 1
• Loss of appetite is not directly mentioned in PBC guidelines but occurs commonly as part of the cholestatic syndrome and progressive liver disease. 1
• The European Association for the Study of the Liver recommends using a structured stepwise approach for fatigue management in PBC, acknowledging fatigue as a major quality-of-life issue requiring systematic treatment. 1

Autoimmune Hepatitis (AIH)

AIH presents with systemic symptoms including fatigue and anorexia, particularly when accompanied by jaundice and active liver inflammation. 2

• The combination of jaundice, elevated transaminases, and positive autoantibodies (ANA ≥1:625) strongly suggests AIH, which characteristically causes constitutional symptoms. 2
• Progressive liver failure from untreated AIH leads to worsening fatigue and appetite loss, making prompt initiation of immunosuppression critical to prevent mortality and morbidity. 2

Prerenal Azotemia and Chronic Kidney Disease

Loss of appetite is extremely common in kidney disease, affecting approximately one-third of chronic dialysis patients and directly correlating with poor outcomes. 3, 4

• In older adults with CKD, loss of appetite is present in 59% of patients and increases significantly when eGFR declines below 45 mL/min/1.73 m². 5
• The risk of death is more than 2-fold higher (RR = 2.23) and hospitalization risk 33% higher among patients extremely bothered by lack of appetite compared to those not bothered. 3
• Anorexia in CKD relates to accumulation of uremic toxins, inflammatory cytokines, and alterations in appetite regulation including amino acid imbalance that creates a hyperserotoninergic state. 4

Starvation Ketoacidosis

Starvation ketoacidosis itself results FROM progressive loss of appetite and can present with severe metabolic acidosis even in patients with normal BMI. 6

• A case report describes a 66-year-old man with BMI 23 kg/m² (previously 28 kg/m²) who developed severe ketoacidosis from inadequate oral intake, demonstrating that significant weight loss may occur over unclear timeframes. 6
• The presence of ketonuria in your patient suggests inadequate caloric intake, which both causes and results from progressive fatigue and anorexia. 6

Clinical Implications

The constellation of ketonuria and conjugated bilirubinuria in a 76-year-old with fatigue and anorexia demands urgent evaluation for:

• Cholestatic liver disease (PBC or AIH) with assessment of alkaline phosphatase, AMA, ANA, and consideration of liver biopsy if AMA-negative or diagnostic uncertainty exists. 1, 2
• Renal function with BUN, creatinine, and eGFR to identify prerenal azotemia or CKD, recognizing that older age, frailty, and depression independently predict loss of appetite in kidney disease. 5
• Nutritional status and recent weight loss, as starvation ketoacidosis can occur with seemingly normal BMI and requires thiamine, intravenous fluids, and careful electrolyte monitoring to prevent refeeding syndrome. 6