In this episode of Hospital Medicine Unplugged, we unpack acute interstitial nephritis (AIN)—a frequently overlooked cause of acute kidney injury (AKI) driven largely by medications, immune reactions, and systemic diseases.

We start with epidemiology clinicians should recognize. AIN accounts for roughly 15–27% of kidney biopsies performed for AKI and about 2.8% of all kidney biopsies overall. Among biopsies done specifically for acute renal failure, AIN represents ~13.5% of cases. Drug-induced AIN dominates the landscape, responsible for 70–90% of biopsy-proven cases, and its incidence appears to be rising—particularly in older adults, where polypharmacy and underutilization of kidney biopsy can obscure the diagnosis.

Next we break down the most common causes.

We then explore the immunologic pathophysiology. AIN is primarily driven by T-cell–mediated hypersensitivity reactions (Type IV) targeting tubular antigens or drug-related antigens processed by tubular epithelial cells. However, IgE-mediated mast cell activation (Type I hypersensitivity) may also contribute in some cases. The resulting interstitial inflammation and edema can rapidly progress to fibrosis, making early recognition and treatment critical for renal recovery.

Histologically, AIN is characterized by interstitial inflammatory infiltrates composed mainly of lymphocytes, macrophages, plasma cells, and sometimes eosinophils, along with tubulitis, interstitial edema, and tubular injury. Glomeruli are typically normal, while interstitial fibrosis and tubular atrophy signal chronicity and worse prognosis. Variants include granulomatous AIN and rare entities like IgM-positive plasma cell tubulointerstitial nephritis.

Clinically, the classic triad of fever, rash, and eosinophilia is now uncommon—present in fewer than 10–15% of patients. Instead, most patients present with nonspecific symptoms such as malaise, nausea, or asymptomatic AKI. Non-oliguric AKI is typical, often accompanied by mild proteinuria and tubular dysfunction.

Diagnosis relies on clinical suspicion, medication review, and supportive laboratory findings. Urinalysis may show sterile pyuria and white blood cell casts, which are more specific for AIN. Eosinophiluria, historically emphasized, is neither sensitive nor specific. Ultimately, kidney biopsy remains the gold standard when the diagnosis is uncertain.

We also review emerging biomarkers that may transform diagnosis. Urinary CXCL9, an interferon-γ–induced chemokine involved in lymphocyte recruitment, has shown excellent diagnostic performance with AUC values up to ~0.94 for AIN detection. Additional candidate biomarkers include urinary TNF-α, IL-9, kidney injury molecule-1 (KIM-1), and soluble C5b-9, reflecting tubular injury and immune activation.

Management begins with immediate withdrawal of the offending drug. If kidney function does not improve within 5–7 days, corticosteroid therapy is often initiated, typically prednisone ~40–60 mg daily (~0.8 mg/kg). Evidence suggests that early steroid therapy—within the first 1–2 weeks—improves renal recovery, while prolonged treatment beyond several weeks offers little additional benefit.

Finally, we discuss prognosis. About 76% of patients achieve some degree of kidney recovery within six months, with complete recovery in roughly half of steroid-treated cases. However, chronic kidney disease remains common, and long-term studies suggest up to 39% of patients may eventually develop end-stage kidney disease. Poor outcomes are associated with delayed diagnosis, prolonged drug exposure, interstitial fibrosis on biopsy, dialysis requirement, and older age.

The key takeaway: acute interstitial nephritis is a common, often medication-related cause of AKI that requires high clinical suspicion, prompt withdrawal of offending drugs, and early consideration of corticosteroids to prevent irreversible kidney damage.

In this episode of Hospital Medicine Unplugged, we break down celiac disease—from epidemiology and modern diagnostic strategies to life-threatening complications and emerging therapies beyond the gluten-free diet.

We start with epidemiology clinicians should know. The global prevalence of celiac disease is ~1.4% based on serology and ~0.7% with biopsy confirmation. Incidence rates are ~17 per 100,000 person-years in women and ~8 per 100,000 in men, with a female-to-male ratio of ~1.8. Importantly, about 70% of cases remain undiagnosed, the so-called “celiac iceberg.” Over recent decades, incidence has increased substantially, rising from <2 per 100,000 annually in the 1980s to >20 per 100,000 in many regions today.

Next we unpack genetic susceptibility and immune pathogenesis. Nearly all patients carry HLA-DQ2 or HLA-DQ8, but these genes alone are insufficient—~40% of the population carries them, yet only 1–3% develop disease, highlighting the role of environmental triggers and additional genetic factors. Gluten exposure leads to immune activation against deamidated gliadin peptides, resulting in small-intestinal inflammation, villous atrophy, and malabsorption.

We then highlight how the clinical presentation has shifted. The classic picture of malabsorption with diarrhea and weight loss is now less common in adults. Instead, non-classical presentations predominate, including iron-deficiency anemia, osteoporosis, abnormal liver enzymes, infertility, and nonspecific GI symptoms. Diarrhea still occurs in ~40–50% of patients, but many adults present with extraintestinal manifestations or even asymptomatic disease.

We also review celiac crisis, a rare but life-threatening presentation requiring hospitalization. Patients develop severe diarrhea, dehydration, electrolyte disturbances, metabolic acidosis, and profound malnutrition. Management requires intravenous fluids, electrolyte replacement, aggressive nutritional support, and sometimes corticosteroids, alongside initiation of a strict gluten-free diet, which leads to improvement in the vast majority of patients.

Diagnosis begins with serologic testing. IgA tissue transglutaminase (tTG-IgA) is the preferred initial screening test, with ~93–95% sensitivity and ~95–98% specificity, and total IgA should be measured simultaneously to detect IgA deficiency. Endomysial antibody testing has near-100% specificity and can confirm the diagnosis. In adults, upper endoscopy with small-bowel biopsy remains the diagnostic standard, demonstrating intraepithelial lymphocytosis, crypt hyperplasia, and villous atrophy.

We then discuss major complications clinicians must recognize. These include osteoporosis, infertility, neurologic complications, hyposplenism, and small-bowel adenocarcinoma. One of the most serious is enteropathy-associated T-cell lymphoma (EATL)—a rare but aggressive malignancy with very poor survival, often arising from type 2 refractory celiac disease.

Refractory celiac disease (RCD) occurs when symptoms and villous atrophy persist despite ≥12 months of strict gluten-free diet.

Management still centers on the gluten-free diet, which leads to symptomatic improvement in ~70% of patients within two weeks, though histologic healing can take months and may remain incomplete in many adults.

Finally, we explore the future of therapy. While diet remains the cornerstone, multiple pharmacologic strategies are in development, including gluten-degrading enzymes, intestinal barrier modulators like larazotide, transglutaminase inhibitors, immune-modulating therapies targeting IL-15, microbiome-based therapies, and even gene-edited wheat with reduced immunogenic gluten.

The takeaway: celiac disease is common, frequently underdiagnosed, and increasingly recognized through non-classical presentations. With improved diagnostics, recognition of severe complications like refractory disease and lymphoma, and a rapidly evolving therapeutic pipeline, management of celiac disease is entering a new era beyond diet alone.

In this episode of Hospital Medicine Unplugged, we tackle polypharmacy and deprescribing—how to recognize problematic medication overload, quantify its harms, and apply structured, patient-centered strategies to safely reduce medication burden.

We begin with definitions that shape clinical practice. Polypharmacy is most commonly defined as the use of ≥5 medications, though definitions vary. Importantly, not all polypharmacy is harmful. “Appropriate polypharmacy” occurs when medications are evidence-based and optimized, while “problematic polypharmacy” arises when medications lack clear benefit or when harms outweigh benefits. Deprescribing is the systematic process of identifying and discontinuing medications whose risks exceed benefits, aligned with a patient’s goals, function, life expectancy, and preferences.

Next we review how common this problem is. Polypharmacy affects 30–40% of community-dwelling older adults, 40–50% of hospitalized older adults, and up to 90% of nursing home residents. Roughly 20–50% of older adults take at least one potentially inappropriate medication (PIM). Risk rises with multimorbidity, female sex, lower socioeconomic status, and each additional chronic disease increases the odds of polypharmacy by nearly 90%.

We then quantify the clinical consequences.

A key driver is the prescribing cascade, where a drug causes side effects that are treated with additional medications. Classic examples include:

To identify problematic medications, we review major screening tools.

We then walk through a practical deprescribing framework. A common 5-step protocol includes:

List all medications and indications

Assess overall risk of drug-related harm

Identify drugs eligible for discontinuation

Prioritize those with highest harm and lowest benefit

Implement tapering and monitor for withdrawal or recurrence

Certain medications require careful tapering to prevent withdrawal syndromes, including benzodiazepines, beta-blockers, antidepressants, corticosteroids, opioids, antiepileptics, clonidine, baclofen, and proton pump inhibitors.

We highlight high-yield deprescribing targets.

We also discuss patient and system barriers. Interestingly, 92% of older adults say they would stop at least one medication if their doctor recommended it, though many fear symptom recurrence or believe medications are necessary.

Finally, we examine solutions that work. Pharmacist-led medication reviews reduce inappropriate medications by 21–35% and lower readmissions, while clinical decision support tools in electronic health records can flag high-risk medications and prompt deprescribing conversations.

The takeaway: polypharmacy is common, harmful, and often reversible. Using structured frameworks, validated screening tools, and shared decision-making, clinicians can safely deprescribe and improve medication safety—especially for older adults with multimorbidity.

In this episode of Hospital Medicine Unplugged, we break down primary hyperparathyroidism (PHPT)—from epidemiology and pathophysiology to modern imaging, surgical indications, and evolving medical therapies.

We start with who gets PHPT and how often it occurs. The condition affects ~0.8–0.9% of the general population, with an incidence of 4–6 cases per 10,000 person-years. It is 2.5 times more common in women, and incidence rises sharply with age, reaching ~12 cases per 10,000 person-years in people aged 70–79. There are also racial disparities, with higher incidence reported in Black populations.

Next we unpack the causes of PHPT. About 80% of cases result from a single parathyroid adenoma, 10–11% from multiple adenomas, <10% from four-gland hyperplasia, and <1% from parathyroid carcinoma. Some cases occur in genetic syndromes such as MEN1, MEN2A, MEN4, and hyperparathyroidism–jaw tumor syndrome.

Clinically, up to 80% of patients in resource-rich settings are now asymptomatic, discovered incidentally through routine lab testing. When symptoms occur, they reflect hypercalcemia and PTH excess, including kidney stones, osteoporosis, gastrointestinal symptoms, and neuromuscular complaints. Many patients also report fatigue, depression, or cognitive symptoms, though the direct causal relationship remains debated.

We then cover complications that drive treatment decisions. PHPT can lead to osteoporosis, fragility fractures, nephrolithiasis, and reduced kidney function. There is also growing evidence linking PHPT with hypertension, left ventricular hypertrophy, and increased cardiovascular risk, though cardiovascular benefit from surgery remains uncertain.

Diagnosis starts with biochemical confirmation—elevated calcium with inappropriately elevated PTH. Imaging is not for diagnosis but for surgical planning. The usual first-line localization strategy combines neck ultrasound with dual-tracer sestamibi scanning, while second-line imaging options such as 4D-CT or 18F-fluorocholine PET/CT offer extremely high sensitivity—up to ~94–99%.

Management centers on parathyroidectomy, which is the definitive treatment. Current guidelines recommend surgery for patients with:

For patients who are not surgical candidates, several medications help control complications:

We also explore normocalcemic primary hyperparathyroidism, an increasingly recognized condition defined by elevated PTH with normal calcium after excluding secondary causes. It may represent an early or milder form of PHPT, often with more multiglandular disease and slightly lower surgical cure rates.

Finally, we highlight critical diagnostic pitfalls and emerging research. Distinguishing PHPT from familial hypocalciuric hypercalcemia (FHH) is essential—FHH shows lifelong mild hypercalcemia and a calcium-to-creatinine clearance ratio <0.01 and does not require surgery. Meanwhile, advanced imaging, genetic testing in younger patients, and combination pharmacotherapy are shaping the future of PHPT care.

The bottom line: primary hyperparathyroidism is common, increasingly detected incidentally, and highly treatable—especially when clinicians recognize surgical indications, use modern imaging strategies, and tailor therapy to complications and patient risk.

In this episode of Hospital Medicine Unplugged, we break down ANCA-associated vasculitis (AAV)—granulomatosis with polyangiitis (GPA), microscopic polyangiitis (MPA), and eosinophilic granulomatosis with polyangiitis (EGPA)—focusing on modern epidemiology, complement-driven pathophysiology, ANCA serotypes, and the rapidly evolving treatment landscape.

We start with epidemiology clinicians should recognize. The global incidence of AAV is ~17 per million person-years, with a prevalence near 198 per million. In the United States, incidence is roughly 3.3 per 100,000, with a prevalence of ~42 per 100,000. Subtype incidence varies: GPA (~9–15/million), MPA (~6/million), and EGPA (~2/million). The mean age at diagnosis is about 61, and rates have increased over the past decades due to greater recognition and widespread ANCA testing.

Next we unpack the pathophysiology that changed therapy. Complement activation—particularly the alternative pathway—plays a central role. C5a drives neutrophil activation and recruitment, creating an inflammatory amplification loop. Low C3 levels correlate with more aggressive disease and worse renal outcomes. This mechanistic insight led to avacopan, an oral C5a receptor antagonist that provides a glucocorticoid-sparing approach to treatment.

We then highlight the importance of ANCA serotype classification. Patients are increasingly categorized by PR3-ANCA vs MPO-ANCA, not just clinical phenotype.

We also review EGPA as a distinct entity. Only ~40% of patients are ANCA-positive. Two clinical subsets exist:

Diagnosis relies on modern ANCA testing and organ evaluation. PR3- and MPO-specific immunoassays are now the preferred screening tests, with ~90–95% sensitivity for active GPA/MPA and >95% specificity. Renal disease occurs in 70–80% of GPA/MPA, typically as pauci-immune necrotizing crescentic glomerulonephritis, while pulmonary disease ranges from nodules and cavitation (PR3) to interstitial lung disease (MPO) and diffuse alveolar hemorrhage.

Management has evolved dramatically. First-line induction therapy combines glucocorticoids with rituximab or cyclophosphamide, with rituximab preferred for most patients—especially PR3-ANCA or relapsing disease. Reduced-dose steroid regimens are now recommended after trials like PEXIVAS, which showed lower infection risk without worse renal outcomes.

We also cover key modern therapies.

For maintenance therapy, rituximab is now the preferred agent, outperforming azathioprine in major trials such as MAINRITSAN and RITAZAREM. Maintenance typically continues 2–4 years, especially in PR3-ANCA patients with high relapse risk.

We finish with EGPA-specific treatment advances. IL-5 pathway inhibitors have transformed care, including mepolizumab and the newer benralizumab, which improve remission rates and allow significant glucocorticoid reduction.

The bottom line: AAV management has shifted toward precision medicine—ANCA serotype classification, complement-targeted therapy, steroid-sparing strategies, and biologic maintenance treatments—dramatically improving survival and long-term outcomes.

In this episode of Hospital Medicine Unplugged, we sprint through fat-soluble vitamins—A, D, E, and K—focusing on how they’re absorbed, why deficiencies happen, and the clinical syndromes hospitalists must recognize early. From intestinal transporters to neurologic deficits and neonatal bleeding, we connect physiology to bedside decision-making.

We start with absorption mechanics, which are more complex than simple passive diffusion. Modern research shows specific intestinal transporters—SR-BI, CD36, NPC1L1, and ABCA1—facilitate uptake of vitamins D, E, and K. Interestingly, vitamin A appears to lack a dedicated membrane transporter for dietary absorption. Absorption is also competitive: vitamins D, E, and K compete with one another, while vitamin A can suppress absorption of other fat-soluble vitamins without being affected itself. This interaction becomes clinically relevant in patients taking high-dose supplements.

Next we tackle vitamin A—vision, epithelial integrity, and immune defense.

Deficiency follows a classic progression:

Vitamin A also regulates epithelial differentiation and T-cell immune function, so deficiency increases susceptibility to infection. Even in high-income settings, restrictive diets or selective eating can lead to severe deficiency and permanent ocular injury.

Toxicity is equally important. Chronic hypervitaminosis A causes:

Sustained doses around 50,000 IU daily for >18 months can produce chronic toxicity.

We then shift to vitamin D—arguably the most clinically debated fat-soluble vitamin.

Vitamin D metabolism follows a three-step pathway:

UVB exposure converts 7-dehydrocholesterol in skin to vitamin D3

Hepatic conversion to 25-hydroxyvitamin D (calcidiol)

Renal activation to calcitriol (1,25-dihydroxyvitamin D)

This active hormone regulates calcium and phosphate homeostasis through tight feedback with parathyroid hormone.

Deficiency is widespread—over one billion people globally. Classic consequences include rickets in children and osteomalacia or osteoporosis in adults, but deficiency also contributes to proximal muscle weakness, increasing fall and fracture risk.

Vitamin D receptors are expressed throughout the body, and observational data link deficiency with cardiovascular disease, autoimmune disease, diabetes, multiple sclerosis, and cancer, although randomized trials show mixed results for extraskeletal benefits.

A key clinical debate remains optimal levels. Many experts advocate serum 25-hydroxyvitamin D concentrations above 40–50 ng/mL, often requiring supplementation beyond traditional recommendations.

Next up: vitamin E—the neurologic protector.

Deficiency primarily manifests with neurologic disease, including:

Severe cases can progress to blindness and dementia.

In cholestatic patients, interpretation requires nuance. Vitamin E levels may appear falsely normal due to hyperlipidemia, so clinicians should measure the vitamin E–to–total lipid ratio instead. Another diagnostic clue is red blood cell acanthocytosis on blood smear.

Toxicity is uncommon but high-dose vitamin E increases bleeding risk, particularly in patients taking anticoagulants.

We close with vitamin K—the coagulation vitamin with expanding roles in vascular biology.

Vitamin K enables γ-carboxylation of clotting factors II, VII, IX, and X and anticoagulant proteins C and S. Deficiency produces functional clotting factor impairment and bleeding once levels fall below ~30 U/dL.

In neonates, vitamin K deficiency bleeding (VKDB) occurs in three forms:

Routine intramuscular vitamin K prophylaxis at birth prevents nearly all cases of late VKDB.

Beyond coagulation, vitamin K activates matrix Gla protein, a powerful inhibitor of vascular calcification, and osteocalcin, which supports bone metabolism.

We also spotlight high-risk populations for fat-soluble vitamin deficiency, including patients with:

Certain medications impair absorption as well—orlistat, cholestyramine, and long-term antibiotics.

Finally, we review laboratory assessment strategies that actually work.

• Vitamin A: serum retinol 1–3 μmol/L normal

Bottom line: fat-soluble vitamins depend on lipid absorption, specialized transporters, and intact hepatobiliary and pancreatic function. Recognizing malabsorption states, neurologic or ocular clues, and appropriate biomarkers is essential to diagnosing deficiency early—before irreversible complications like blindness, neuropathy, fractures, or intracranial hemorrhage occur.

In this episode of Hospital Medicine Unplugged, we sprint through thalassemia—an inherited hemoglobinopathy defined by reduced or absent globin chain production, ineffective erythropoiesis, and chronic anemia. We break down the genetics, pathophysiology, clinical spectrum, and why this disorder remains the most common monogenic disease worldwide.

We start with the big picture. About 5% of the global population carries an α-thalassemia allele and 1.5% carries a β-thalassemia allele, with roughly 1.3 million people living with disease and ~40,000 affected infants born annually. The condition clusters across malaria-endemic regions—from sub-Saharan Africa and the Mediterranean to the Middle East, South Asia, and Southeast Asia—because the carrier state provides partial protection against malaria. Migration has increasingly brought thalassemia to North America and Europe, expanding its global clinical impact.

Next, we revisit normal hemoglobin physiology. Adult hemoglobin (HbA) is α₂β₂, with smaller fractions of HbA₂ (α₂δ₂) and HbF (α₂γ₂). During infancy, the body transitions from fetal hemoglobin to adult hemoglobin as γ-globin declines and β-globin production increases, regulated by transcription factors such as BCL11A and KLF1. Balanced α- and β-chain production is essential—when the balance breaks, unpaired globin chains accumulate, precipitate, and damage developing red cells, driving ineffective erythropoiesis.

We then dive into the genetic architecture.

• α-thalassemia is usually caused by gene deletions affecting HBA1 or HBA2.

Mutations are classified as:

Severity depends on genotype, but genetic modifiers matter—coinherited α-thalassemia, increased HbF production, or α-globin gene duplications can significantly alter disease expression.

Next, we map the clinical classification.

Alpha thalassemia spectrum:

Beta thalassemia spectrum:

Compound disorders add complexity, including HbE-β thalassemia and sickle-β thalassemia, where severity depends on the interacting mutations.

Then we unpack the pathophysiology driving complications.

Excess unpaired globin chains cause oxidative damage and premature death of erythroid precursors, leading to:

Chronic erythropoietin stimulation leads to skeletal deformities—frontal bossing, maxillary hypertrophy, and long-bone abnormalities.

Iron overload develops through two major pathways:

The downstream damage is systemic: cardiomyopathy, arrhythmias, liver fibrosis and cirrhosis, endocrine failure (growth delay, diabetes, hypothyroidism, hypoparathyroidism), osteoporosis, and thrombosis risk.

We close with the clinical spectrum.

• Trait: usually asymptomatic with incidental microcytosis

Bottom line: thalassemia is a disorder of globin chain imbalance leading to ineffective erythropoiesis, hemolysis, marrow expansion, and iron overload. Understanding the genetics, modifiers, and pathophysiology is essential to predicting severity, guiding transfusion strategies, and preventing the devastating end-organ complications of chronic iron toxicity.

In this episode of Hospital Medicine Unplugged, we sprint through ankylosing spondylitis and axial spondyloarthritis—recognize inflammatory back pain early, understand the disease spectrum from non-radiographic to radiographic disease, and treat aggressively to prevent structural damage and disability.

We begin with the modern concept of axial spondyloarthritis (axSpA), which represents a disease spectrum rather than a single condition. At one end is non-radiographic axial spondyloarthritis (nr-axSpA)—patients with typical symptoms but without definitive radiographic sacroiliitis. At the other end is radiographic axial spondyloarthritis (r-axSpA), historically known as ankylosing spondylitis, where structural changes in the sacroiliac joints are visible on X-ray.

Globally, axial spondyloarthritis affects roughly 0.3% to 1.4% of the population, with about 1% prevalence in the United States. Disease onset typically occurs early in life—more than 80% of patients develop symptoms before age 30. Radiographic disease is more common in men, while non-radiographic disease occurs equally in men and women.

A major challenge in this condition is diagnostic delay, which averages nearly seven years from symptom onset. This delay contributes to progressive inflammation, structural damage, and functional impairment before effective therapy is started.

The pathogenesis of axial spondyloarthritis involves a combination of genetic susceptibility, immune dysregulation, and environmental triggers. The strongest genetic risk factor is HLA-B27, present in 80–90% of patients with ankylosing spondylitis.

Several mechanisms have been proposed to explain how HLA-B27 contributes to disease:

• Presentation of arthritogenic peptides to CD8+ T cells

At the center of the inflammatory cascade lies the IL-23 / IL-17 axis, which drives activation of Th17 cells and production of pro-inflammatory cytokines including IL-17 and TNF-α. Mechanical stress at the entheses—the sites where ligaments and tendons attach to bone—triggers inflammation, making enthesitis the hallmark pathological process. Chronic inflammation eventually stimulates pathologic new bone formation, producing syndesmophytes and spinal ankylosis.

Clinically, the hallmark symptom is inflammatory back pain, present in more than 80% of patients. Key features include:

• Onset before age 45 years

Extra-articular manifestations are common and often provide diagnostic clues.

The most frequent is acute anterior uveitis, occurring in 25–30% of patients. Episodes typically present with sudden eye pain, redness, photophobia, and blurred vision.

Other associated conditions include:

• Inflammatory bowel disease (5–10%)

Because early disease may not show radiographic damage, classification relies on modern criteria.

The Modified New York Criteria require definite radiographic sacroiliitis and therefore identify only advanced disease.

In contrast, the ASAS classification criteria for axial spondyloarthritis allow earlier diagnosis. These criteria apply to patients with chronic back pain lasting ≥3 months with onset before age 45 and include two diagnostic pathways:

• Imaging arm: sacroiliitis on MRI or radiograph plus ≥1 SpA feature

These criteria have approximately 83% sensitivity and 84% specificity, enabling detection of earlier disease stages.

Monitoring disease activity is critical to guide treatment decisions. The Ankylosing Spondylitis Disease Activity Score (ASDAS) is the preferred measure because it incorporates both patient-reported symptoms and inflammatory markers such as CRP.

ASDAS categories include:

• Inactive disease: <1.3

Management begins with non-pharmacologic therapy, which remains foundational for all patients. This includes structured exercise programs, physical therapy, posture training, and smoking cessation, as smoking is associated with worse radiographic progression and poorer treatment response.

First-line pharmacologic therapy is NSAIDs, which reduce pain and inflammation. Continuous therapy may be more effective than intermittent use, although fewer than one quarter of patients achieve complete symptom control with NSAIDs alone.

For patients with persistent disease activity, biologic therapy is the next step.

TNF inhibitors were the first biologics proven effective, producing ASAS20 response rates of roughly 60% and reducing radiographic progression.

More recently, IL-17 inhibitors such as secukinumab and ixekizumab have shown comparable efficacy. A newer agent, bimekizumab, blocks both IL-17A and IL-17F, offering promising results.

JAK inhibitors, including upadacitinib and tofacitinib, provide an oral treatment option and demonstrate response rates exceeding 50%, though regulatory agencies caution about risks including cardiovascular events and infections.

Despite the strong genetic association with IL-23, IL-23 inhibitors have not demonstrated clinical benefit in axial spondyloarthritis, highlighting the complexity of immune signaling pathways.

Long-term outcomes vary widely. The strongest predictor of future structural damage is existing syndesmophytes at baseline. Other poor prognostic factors include male sex, smoking, early hip involvement, and persistent systemic inflammation.

Complications can also arise from the structural rigidity of the spine. Osteoporosis and vertebral fractures occur in up to 10% of patients, meaning new spinal pain—even after minor trauma—should prompt evaluation for fracture.

We close with the key clinical takeaways:

• Axial spondyloarthritis is a spectrum ranging from non-radiographic disease to classic ankylosing spondylitis

Early recognition and treatment are critical—because once structural ankylosis develops, damage is irreversible.

In this episode of Hospital Medicine Unplugged, we sprint through prosthetic heart valves—how to choose between mechanical and bioprosthetic valves, manage anticoagulation safely, recognize complications, and navigate the expanding role of transcatheter valve replacement.

We begin with the two major categories of prosthetic valves: mechanical valves and bioprosthetic (tissue) valves. Mechanical valves are constructed from durable materials such as pyrolytic carbon and are designed to last decades, but their thrombogenic surface requires lifelong anticoagulation with a vitamin K antagonist.

Anticoagulation targets depend on valve position and risk factors.

In most patients, low-dose aspirin (75–100 mg daily) is added to vitamin K antagonist therapy to further reduce thromboembolic risk.

Bioprosthetic valves, in contrast, are made from porcine valves or bovine pericardium. These valves are less thrombogenic, which allows for short-term anticoagulation (typically 3–6 months) after implantation followed by lifelong antiplatelet therapy with aspirin. The trade-off is durability—structural valve degeneration (SVD) eventually occurs due to calcification, fibrosis, or leaflet tearing.

Choosing between valve types requires balancing durability versus anticoagulation risk. Mechanical valves generally offer better long-term durability, while bioprosthetic valves avoid lifelong anticoagulation but may require future reoperation.

Age is one of the most important factors in valve selection. Evidence from large observational studies demonstrates that mechanical valves provide survival advantages in younger patients, particularly:

Current ACC/AHA guidelines generally recommend:

The treatment landscape has changed dramatically with the development of transcatheter aortic valve replacement (TAVR). Initially reserved for patients with prohibitive surgical risk, TAVR is now widely used across risk groups.

Landmark trials such as PARTNER 3 demonstrated that in low-risk patients with severe aortic stenosis, TAVR produced outcomes comparable to surgical valve replacement at five years. TAVR offers advantages including lower rates of atrial fibrillation and bleeding, though it carries higher risks of paravalvular regurgitation and pacemaker implantation.

Guidelines now recommend:

Anticoagulation management remains one of the most critical aspects of prosthetic valve care. Direct oral anticoagulants (DOACs are contraindicated in mechanical valves). The RE-ALIGN trial showed increased thromboembolic and bleeding complications with dabigatran compared with warfarin, leading to early termination of the study. More recently, the PROACT Xa trial evaluating apixaban in patients with On-X mechanical valves also demonstrated excess thromboembolic events.

For bioprosthetic valves, however, DOACs may be used in patients who develop atrial fibrillation, although long-term data remain limited.

Despite technological advances, prosthetic valves carry important complications. One of the most serious is prosthetic valve endocarditis (PVE), which is associated with high mortality. Management requires prolonged intravenous antibiotics, typically for at least six weeks, and surgery may be required for heart failure, uncontrolled infection, or large vegetations.

Another major complication is prosthetic valve thrombosis, particularly with mechanical valves. Management depends on clinical severity and thrombus size. Options include urgent surgery or low-dose, slow-infusion fibrinolysis, with modern thrombolytic protocols achieving over 90% success rates and low complication rates.

A subtler but clinically important issue is prosthesis–patient mismatch (PPM). This occurs when the effective orifice area of the prosthetic valve is too small relative to the patient’s body surface area, creating persistent obstruction despite valve replacement. Severe PPM is defined as indexed effective orifice area <0.65 cm²/m² and is associated with higher mortality, reduced left ventricular mass regression, and worse heart failure outcomes.

Certain populations require special consideration. Pregnancy with mechanical valves carries substantial maternal and fetal risk due to the competing challenges of anticoagulation and thrombosis prevention. Warfarin provides the most reliable valve protection but carries risk of embryopathy at higher doses. For women planning pregnancy, bioprosthetic valves are often preferred, even though they may require earlier replacement.

Finally, structural valve degeneration is the major limitation of bioprosthetic valves. The process occurs gradually and progresses through stages—from early structural changes without hemodynamic impact to severe valve dysfunction requiring reintervention. Risk factors for accelerated degeneration include younger age, renal disease, hypertension, hyperparathyroidism, and prosthesis–patient mismatch.

Because degeneration can occur silently, lifelong surveillance with periodic echocardiography is essential for all patients with prosthetic valves.

We close with the key clinical takeaways:

• Mechanical valves offer durability but require lifelong warfarin therapy

Prosthetic valve management is a lifelong process—successful outcomes depend not only on the procedure itself but on careful anticoagulation, surveillance, and early recognition of complications.

In this episode of Hospital Medicine Unplugged, we sprint through asbestosis—understand how inhaled fibers trigger progressive pulmonary fibrosis, recognize key radiographic features, and manage patients with attention to malignancy risk and progressive fibrotic disease.

We start with pathophysiology, where the story begins decades before symptoms appear. After inhalation, asbestos fibers deposit in the distal airways and alveoli. Alveolar macrophages attempt to engulf these fibers, but many fibers are too long to be fully internalized—triggering “frustrated phagocytosis.” This leads to persistent macrophage activation and release of inflammatory mediators including TNF-α, IL-1, and TGF-β. At the same time, reactive oxygen species form both from macrophage activation and from iron on the fiber surface, amplifying oxidative injury.

A key early event is alveolar epithelial cell apoptosis, driven by mitochondrial injury, p53-mediated pathways, and endoplasmic reticulum stress. Loss of epithelial integrity and chronic inflammation stimulate fibroblast activation and collagen deposition, ultimately producing the progressive interstitial fibrosis that defines asbestosis.

Not all asbestos fibers carry the same risk. Amphibole fibers—particularly crocidolite and amosite—are far more fibrogenic and carcinogenic than chrysotile fibers. Their needle-like shape, durability, and resistance to biological clearance allow them to persist in lung tissue for decades. Fiber dimensions matter: long fibers (>10–20 μm) and extremely thin fibers (<0.25 μm) pose the highest disease risk because they reach distal lung regions and resist macrophage clearance.

One of the defining features of asbestos disease is extraordinary latency. Clinical asbestosis usually develops 20–40 years after the first exposure, with peak disease occurrence around 40–45 years after exposure begins. Lung cancer tends to occur earlier, typically 30–35 years after exposure. Disease progression varies—some patients remain stable while others develop progressive fibrotic lung disease with significant annual declines in FVC, particularly those with fibrotic patterns on HRCT.

Diagnosis relies on a combination of exposure history, latency, imaging, and pulmonary function testing. According to consensus guidelines, the diagnosis requires:

• Documented asbestos exposure

While chest X-ray can detect classic small irregular opacities, high-resolution CT is far more sensitive. Key HRCT findings include:

• Subpleural curvilinear lines (one of the most specific findings)

Importantly, most patients with asbestosis also show benign pleural abnormalities, such as pleural plaques or diaphragmatic pleural thickening, which strongly support asbestos exposure.

Unfortunately, no disease-modifying therapies are currently approved specifically for asbestosis. Management traditionally focuses on supportive care, including:

• Smoking cessation

However, the treatment landscape is evolving. Because asbestosis can behave like other progressive fibrosing interstitial lung diseases, antifibrotic therapies are increasingly considered for patients with progressive disease. Nintedanib, approved for progressive fibrosing ILD, may slow lung function decline in patients with progressive asbestosis. Early studies of pirfenidone suggest acceptable safety and potential benefit, though definitive evidence remains limited.

Another critical dimension of asbestos exposure is malignancy risk. Asbestos causes two to six times more lung cancers than mesotheliomas, making asbestos-related lung cancer a major public health burden. The interaction with smoking is particularly dangerous: asbestos and smoking have a synergistic effect on lung cancer risk. In exposed workers, the combined effect can increase lung cancer mortality more than 30-fold.

Importantly, asbestos exposure increases lung cancer risk even in nonsmokers, but smoking cessation dramatically reduces risk over time. Within 10 years of quitting, lung cancer mortality drops significantly, and after 30 years, risk approaches that of never-smokers.

For malignant mesothelioma, amphibole fibers again carry the greatest risk. Crocidolite exposure has the highest potency, and mesothelioma risk continues to rise 40–50 years after initial exposure.

Because treatment options for mesothelioma remain limited, prevention and early detection are essential. The most effective intervention is elimination of exposure, enforced through occupational safety regulations, air monitoring, and protective equipment.

For individuals with significant asbestos exposure, low-dose CT screening can help detect early lung cancers, improving survival outcomes. Unfortunately, routine screening for mesothelioma is not currently recommended, as effective early detection strategies remain lacking.

We close with the key clinical takeaways:

• Asbestosis results from chronic macrophage activation and epithelial injury triggered by persistent asbestos fibers

Asbestosis remains a preventable occupational disease, but its long latency means clinicians continue to encounter its consequences decades after exposure—making exposure history, imaging recognition, and malignancy surveillance critical in modern clinical practice.