Primary sclerosing cholangitis (PSC) is a rare cholestatic disease that causes fibrosis and strictures of the bile ducts. It is primarily diagnosed in males between 30 and 40 years of age. Its presentation in elderly females is uncommon and represents a diagnostic challenge. The objective of this study is to present a clinical case of PSC with an atypical presentation in an elderly female with associated cholelithiasis. A 74-year-old female with no medical history presented with jaundice, dark urine, acholia, and pruritus. She was admitted to the emergency department with jaundice and a cholestatic pattern. Initial imaging studies identified cholecystitis and possible extrinsic compression of the bile duct by the gallbladder, mimicking Mirizzi syndrome. Magnetic resonance cholangiopancreatography identified a focal biliary stricture, but serological markers for PSC were negative. Due to persistent pain, a cholecystectomy and liver biopsy were performed. The liver biopsy was positive for PSC. PSC should be considered in elderly patients with persistent cholestatic jaundice despite concomitant gallstone disease. Characteristic cholangiographic findings, together with histopathological evaluation and exclusion of secondary causes, support the diagnosis in atypical presentations.

Autoimmune hepatitis (AIH) is a chronic immune-mediated liver disease diagnosed by the clustering of compatible biochemical, serological, and histological features after exclusion of competing causes. Concurrent biliary obstruction or drug-induced injury can obscure the underlying autoimmune process and misdirect the initial diagnosis toward a purely obstructive or toxic cause. A 65-year-old woman with a remote cholecystectomy presented with one week of painless jaundice, dark urine, fatigue, and pruritus on a background of a year of slowly progressive aminotransferase elevation. She had also completed an unprescribed two-week course of oral ivermectin shortly before presentation. Admission studies showed marked hepatocellular injury (aspartate aminotransferase (AST): 2,109 U/L, alanine aminotransferase (ALT): 1,652 U/L), conjugated hyperbilirubinemia (total bilirubin: 8.4 mg/dL), mildly elevated alkaline phosphatase (ALP) (253 U/L), hypergammaglobulinemia (globulin: 5 g/dL; subsequent immunoglobulin G (IgG): 2,925 mg/dL), and an international normalized ratio (INR) of 1.6. With a negative viral hepatitis panel, a normal acetaminophen level, and bland cross-sectional imaging, empiric intravenous corticosteroids were begun on hospital day 2. Aminotransferases and bilirubin fell briskly over the next 72 hours, before any mechanical relief of obstruction. Magnetic resonance cholangiopancreatography (MRCP) on hospital day 4 revealed a 7-mm common bile duct stone, extracted at endoscopic retrograde cholangiopancreatography on hospital day 5. Smooth muscle antibody (SMA) returned at a titer of ≥1:640, with negative antinuclear antibodies (ANA) and antimitochondrial antibodies (AMA), a profile consistent with type 1 AIH. By a simplified International Autoimmune Hepatitis Group (IAIHG) score of 6, the combination of high-titer SMA, markedly elevated IgG, and a corticosteroid response that preceded biliary decompression identified AIH as the most likely dominant driver of injury, with choledocholithiasis as a concurrent second insult and ivermectin as a possible contributor of indeterminate magnitude. Obstructive imaging findings can anchor clinicians away from a concurrent, treatable autoimmune process, and a corticosteroid response that precedes mechanical decompression carries genuine diagnostic weight. Because histology was not obtained during the index admission, the relative contributions of the biliary stone and ivermectin cannot be fully excluded; long-term follow-up, including confirmatory biopsy and a structured trial of corticosteroid withdrawal, will clarify whether the disease is best classified as idiopathic AIH unmasked by concurrent insults or as a drug-related variant.

Postpartum autoimmune hepatitis (AIH) is a rare but serious condition triggered by immune rebound after delivery. Diagnosis is typically supported by elevated immunoglobulins and positive autoimmune markers; however, seronegative presentations remain diagnostically challenging. We present the fourth reported worldwide case of seronegative postpartum AIH in a 36-year-old woman who developed jaundice, pruritus, pale stools, and dark urine 4 months after delivery. Laboratory evaluation revealed severe hepatocellular injury with aspartate aminotransferase 1373 U/L, alanine aminotransferase 2137 U/L, and marked hyperbilirubinemia. Viral, toxic, metabolic, and rheumatologic investigations were negative, while autoimmune serologies and immunoglobulin levels remained normal. Imaging demonstrated hepatomegaly without biliary obstruction or vascular abnormalities. Liver biopsy revealed acute-on-chronic autoimmune-mediated hepatitis with necrosis, confirming seronegative postpartum AIH. This case emphasizes seronegative AIH as a critical consideration in postpartum acute hepatitis, with liver biopsy essential for diagnosis and early treatment.

Background/Objectives: Tirzepatide, a dual glucose-dependent insulinotropic polypeptide and glucagon-like peptide-1 receptor agonist, is increasingly used for glycemic control and weight reduction and has a generally favorable hepatic safety profile. However, rare cases of clinically significant drug-induced liver injury have been reported. We report a case of severe hepatocellular injury during tirzepatide therapy and compare it with previously reported cases. Case Presentation: A 36-year-old man developed gastrointestinal symptoms, dark urine, and severe hepatocellular injury approximately 5 weeks after starting tirzepatide for weight reduction, shortly after dose escalation from 2.5 mg to 5 mg weekly and amid rapid weight loss of approximately 10 kg. Extensive evaluation excluded viral, autoimmune, metabolic, biliary, and structural causes, with no competing medication or supplement exposure identified. Tirzepatide was discontinued, and clinical and biochemical status improved rapidly. The Roussel Uclaf Causality Assessment Method (RUCAM) score was 7, indicating probable drug-induced liver injury. Discussion: Previously reported cases demonstrate heterogeneous biochemical patterns and severity, ranging from mild hepatocellular injury to mixed or cholestatic presentations and acute liver failure requiring transplantation. The mechanism remains uncertain. An idiosyncratic drug reaction is the most plausible explanation, while rapid weight loss, dose escalation, and hepatic steatosis may represent susceptibility modifiers rather than established causes. Conclusions: Tirzepatide-associated liver injury appears rare but can be clinically severe. Clinicians should remain alert to the possibility of drug-induced liver injury when unexplained hepatic symptoms or liver biochemical abnormalities arise during treatment.

Hepatoerythropoietic porphyria (HEP) is a rare autosomal recessive disorder of heme biosynthesis caused by severe deficiency of uroporphyrinogen decarboxylase (UROD). It typically presents in infancy or early childhood with marked photosensitivity, skin fragility, blistering, dyspigmentation, hypertrichosis, and dark urine. We report a girl from Brazil who developed blistering and ulcerative lesions of the face and upper extremities beginning at 10 months of age, along with dark urine and gray discoloration of the teeth. She was 2.5 years old when first evaluated at the Massachusetts General Hospital Porphyria Center. Prior genetic testing in Brazil had already identified two UROD variants, c.239C>G (p.Ala80Gly) and c.464C>T (p.Ala155Val). At our center, erythrocyte UROD activity was markedly reduced to approximately 5% of normal, and plasma, urine, stool, and erythrocyte porphyrins were all substantially elevated, confirming the diagnosis of HEP. Erythrocyte protoporphyrin was 83.5% zinc-chelated. The patient also had persistent mild hepatosplenomegaly and mild transaminase elevation. Management included strict photoprotection and sequential trials of cholestyramine and cimetidine, followed by serial therapeutic phlebotomy while continuing cimetidine. Neither cholestyramine nor therapeutic phlebotomy was associated with clear biochemical improvement, whereas cimetidine was temporally associated with a decline in urinary porphyrins, although other biomarkers were more variable. This case highlights the importance of considering HEP in children with blistering lesions on sun-exposed skin.

Elevated creatine kinase (CK) levels may occur in a wide range of clinical conditions including skeletal muscle injury, inflammatory myopathies, medication-associated myotoxicity, rhabdomyolysis, and strenuous physical activity. Distinguishing clinically significant muscle injury from transient physiologic hyperCKemia may be particularly challenging in asymptomatic patients undergoing routine laboratory surveillance. We report the case of a 62-year-old African American male clinical trial participant in whom marked asymptomatic hyperCKemia was identified through protocol-driven safety monitoring during long-term study participation. Serial laboratory assessments identified a marked isolated serum CK elevation (2694 U/L) with preserved creatinine clearance and stable renal function throughout the monitoring period. Approximately three weeks prior to the peak laboratory abnormality, the participant reported intensification of physical exercise activity. Despite marked CK elevation, the participant denied myalgia, muscle weakness, dark urine, decreased urine output, chest pain, palpitations, dyspnea, or constitutional symptoms. Twelve-lead electrocardiography demonstrated normal sinus rhythm with nonspecific low-amplitude T-wave abnormalities without clinically significant arrhythmias or acute ischemic abnormalities. Review of temporal relationships, concomitant medications, available safety data, and the Investigator's Brochure did not support the investigational product as a likely contributor to the laboratory abnormalities. The participant remained clinically stable with preserved renal function and spontaneous improvement in laboratory abnormalities during continued monitoring. This case highlights the importance of contextual interpretation of marked asymptomatic CK elevation and demonstrates how protocol-driven safety monitoring can facilitate early identification and evaluation of clinically silent laboratory abnormalities in clinical trial participants.

Rhabdomyolysis is a potentially life-threatening condition characterized by skeletal muscle breakdown and release of intracellular contents into the systemic circulation. Exertional rhabdomyolysis (ER) most commonly occurs after high-intensity exercise involving large muscle groups, but cases related to lower intensity or repetitive activity have also been reported. We describe a case of acute ER in a previously healthy 36-year-old man who developed the condition after initiating a workout regimen for erectile dysfunction that included gluteal exercises and pelvic floor muscle training (PFMT), including Kegel exercises, demonstrated in YouTube (Google, San Bruno, CA) videos. The patient presented with dark, reddish-brown urine and mild soreness in the hips and lower back several days after a workout consisting of repetitive pelvic floor contractions, glute bridges, and pelvic tilts. He noted that he had difficulty walking two days after completing the exercises, which had resolved by the time of his visit. Physical examination was unremarkable; however, laboratory testing revealed markedly elevated creatine kinase levels (>22,000 U/L) with associated transaminase elevation. Urinalysis demonstrated positive blood on dipstick without microscopic hematuria, consistent with myoglobinuria. The patient was admitted for aggressive intravenous hydration and monitored closely, with gradual improvement in laboratory values during a four-day hospital course and full recovery without renal complications. This case highlights an uncommon presentation of ER following initiation of an unsupervised exercise regimen that included PFMT, along with gluteal and core exercises. It illustrates that even exercises generally considered lower impact may contribute to significant muscle injury when performed without appropriate instruction and gradual conditioning or in previously unaccustomed individuals. Awareness of atypical triggers and subtle clinical presentations may help clinicians recognize rhabdomyolysis earlier and initiate prompt treatment to prevent serious complications.

In patients with end-stage renal disease (ESRD), diagnosing jaundice can be challenging because uremic skin changes and anuria may obscure classic signs such as scleral icterus and dark urine. We report a rare case in which discoloration of the hemodialysis circuit provided the first clue to occult hyperbilirubinemia. A 35-year-old woman with ESRD secondary to lupus nephritis presented for hemodialysis with features of uremia and fluid overload. Physical examination revealed no scleral icterus or skin discoloration. After a 2-hour session using a low-flux polysulfone dialyzer, a striking yellowish discoloration of the dialyzer membrane was noted. Laboratory evaluation, prompted by this observation, revealed marked unconjugated hyperbilirubinemia, elevated lactate dehydrogenase, low haptoglobin, and hemoglobinuria, confirming intravascular hemolysis complicating systemic lupus erythematosus. The yellow discoloration was attributed to the adsorption of bilirubin-albumin complexes onto the hollow fibers of the dialyzer membrane. The patient was treated with high-dose oral prednisolone for autoimmune hemolytic anemia associated with a lupus flare. Over three weeks and six subsequent dialysis sessions, hemolysis markers normalized, the yellow discoloration resolved, and her clinical condition improved significantly. Yellowish staining of the dialyzer membrane is an uncommon but important bedside sign of hyperbilirubinemia in patients undergoing dialysis. This extracorporeal indicator may reveal serious conditions such as intravascular hemolysis or hepatic dysfunction when conventional clinical signs are absent. Careful inspection of the dialysis circuit can facilitate early diagnosis, prompt treatment, and improved outcomes in this vulnerable population.

Alkaptonuria (AKU) is a rare metabolic disorder caused by homogentisate 1,2-dioxygenase deficiency, leading to systemic accumulation of homogentisic acid (HGA) and progressive tissue degeneration characterized by dark urine, ochronosis, and severe osteoarthropathy. Chronic exposure to HGA promotes oxidative stress, chondroptosis, secondary amyloidosis, and impaired autophagy, an essential process for maintaining chondrocyte homeostasis. This study investigated the mechanisms potentially involved in autophagy dysregulation in AKU using the human C20/A4 chondrocyte line treated with 0.1 mM HGA, an established in vitro model of the disease. The findings were then verified using chondrocyte cells and cartilage tissue obtained from AKU biopsies. HGA treatment induced a time-dependent increase in oxidative stress, evidenced by elevated ROS levels, 4-HNE accumulation, and overproduction of mitochondrial superoxide. Autophagy assessment showed an early increase in autophagy-related markers, with increased LC3 and p62 expression and enhanced lysosomal biogenesis (LAMP1). However, prolonged HGA exposure was associated with reduced LC3/LAMP1 colocalization, persistent p62 accumulation, altered acidic compartment staining, and accumulation of autophagy-related structures, supporting a dysregulation of the autophagy-lysosomal pathway. Live-cell imaging further supported a transition from functional autophagy to lysosomal failure under chronic oxidative stress. Overall, this study suggests that prolonged HGA exposure disrupts the interplay between oxidative stress and autophagic flux. The progressive collapse of these adaptive mechanisms may contribute to chondrocyte degeneration and to the pathogenesis of cartilage damage in AKU.