Differential Diagnosis for Hemoptysis, Elevated Liver Enzymes, and Skin Lesions
The most critical diagnosis to consider in a patient presenting with this triad is systemic lupus erythematosus (SLE), followed by sarcoidosis and disseminated histoplasmosis, as these conditions can simultaneously affect the lungs, liver, and skin with potentially life-threatening complications if untreated.
Primary Differential Diagnoses
Systemic Lupus Erythematosus (SLE)
SLE should be at the top of your differential when this triad presents together. 1, 2
- Pulmonary manifestations: Hemoptysis occurs in up to 17% of SLE cases, typically from bacterial or opportunistic infections, uremia, pulmonary embolism, or alveolar hemorrhage 3
- Hepatic involvement: Elevated liver enzymes can occur in SLE, though less commonly than other manifestations 4
- Cutaneous findings: Maculopapular, erythematous, or violaceous skin lesions are characteristic; acute cutaneous lupus, subacute cutaneous lupus (highly photosensitive, associated with anti-Ro/SSA antibodies), and chronic cutaneous lupus (including discoid lesions) are all possible 5, 1
Essential diagnostic workup for SLE: 1
- Skin biopsy for histological confirmation
- Autoantibody panel: ANA, anti-dsDNA, anti-Ro/SSA, anti-La/SSB, anti-RNP, anti-Sm
- Complement levels (C3, C4)
- Complete blood count, ESR, CRP (CRP >50 mg/L suggests superimposed infection rather than disease activity) 6
- Urinalysis with protein/creatinine ratio
- Serum creatinine and albumin
Sarcoidosis
Sarcoidosis is a strong consideration given its propensity for multi-organ granulomatous involvement. 5
- Pulmonary manifestations: Bilateral hilar adenopathy, perilymphatic nodules, and upper lobe infiltrates are highly probable features; hemoptysis can occur though less common 5
- Hepatic involvement: Hepatomegaly and alkaline phosphatase >3× upper limit of normal are probable features; granulomatous hepatitis causes elevated liver enzymes 5
- Cutaneous findings: Lupus pernio (highly probable), maculopapular/erythematous/violaceous lesions, subcutaneous nodules, and erythema nodosum (as part of Löfgren's syndrome) are characteristic 5
Key diagnostic features: 5
- Elevated ACE level (>50% above upper limit of normal)
- BAL lymphocytosis or elevated CD4:CD8 ratio
- Non-caseating granulomas on biopsy
- Bilateral hilar adenopathy on chest imaging
Disseminated Histoplasmosis
Progressive disseminated histoplasmosis must be considered, particularly in immunocompromised patients or those from endemic areas. 5
- Pulmonary manifestations: Acute pulmonary histoplasmosis can cause hemoptysis, particularly with cavitary disease 5
- Hepatic involvement: Hepatosplenomegaly and progressive elevation of hepatic enzyme levels are characteristic of disseminated disease 5
- Cutaneous findings: Mucosal ulcers and skin lesions provide important diagnostic clues 5
Diagnostic approach: 5
- Demonstration of granulomas with yeasts in extrapulmonary tissues
- Culture of Histoplasma capsulatum
- Persistent antigenuria and/or antigenemia
- Serology (positive IgG and IgM antibodies)
Secondary Differential Diagnoses
Granulomatosis with Polyangiitis (GPA)
- Small-vessel ANCA-associated vasculitis can present with hemoptysis, skin lesions, and less commonly hepatic involvement 5
- Distinguished from sarcoidosis by ANCA positivity and different histopathologic features 5
Drug-Induced Liver Injury (DILI) with Concurrent Pulmonary Disease
- Medical history of hepatotoxic compounds (drugs, over-the-counter medications, herbals) is essential 5
- ALT >5× ULN or ALT >3× ULN with bilirubin >2× ULN suggests DILI 5
- Skin reactions can occur with drug hypersensitivity
- Hemoptysis would require separate pulmonary etiology
Autoimmune Hepatitis (AIH) with Extrahepatic Manifestations
- Elevated AST/ALT, hypergammaglobulinemia, increased IgG 5
- Positive ANA, anti-SMA, anti-SLA/LP (type 1) or anti-LKM 1/3, anti-LC-1 (type 2) 5
- Can have cutaneous manifestations and rarely pulmonary involvement
Primary Biliary Cirrhosis (PBC) with Overlap Syndrome
- Highly positive antimitochondrial M2 antibodies distinguish PBC 4
- Can rarely coexist with SLE 4
- Pruritus is the most common cutaneous symptom; xanthelasmas and pigmentary changes occur 7
Critical Diagnostic Algorithm
Step 1: Immediate Assessment 5
- Quantify hemoptysis severity (massive vs. non-massive)
- Assess hemodynamic stability
- Obtain chest radiograph and basic labs (CBC, comprehensive metabolic panel, coagulation studies)
Step 2: Advanced Imaging 5
- CT chest with IV contrast is the preferred initial imaging for hemoptysis evaluation (identifies cause in 83-94% of cases) 5
- Abdominal imaging if hepatomegaly or splenomegaly present
Step 3: Targeted Laboratory Workup 1, 5
- For SLE: ANA, anti-dsDNA, anti-Ro/SSA, anti-La/SSB, complement levels, urinalysis 1
- For sarcoidosis: ACE level, serum calcium, BAL with CD4:CD8 ratio 5
- For histoplasmosis: Histoplasma antigen (urine/serum), antibody testing, fungal cultures 5
- For vasculitis: ANCA panel
- For hepatic etiology: Viral hepatitis panel, autoimmune hepatitis markers, antimitochondrial antibodies 5
- Skin biopsy is mandatory for definitive diagnosis of cutaneous manifestations 1
- Bronchoscopy with BAL and/or transbronchial biopsy for pulmonary lesions 5
- Liver biopsy may be necessary if diagnosis remains unclear after non-invasive testing 5
Common Pitfalls to Avoid
- Do not rely solely on ANA testing: ANA can be positive in multiple conditions and does not confirm SLE 1
- Do not assume hemoptysis in SLE is always from lupus: Infection (bacterial, tuberculosis, opportunistic) is the most common cause and must be excluded 3
- Do not overlook drug-induced causes: Always obtain detailed medication history including over-the-counter and herbal supplements 5
- Do not delay bronchoscopy in massive hemoptysis: Airway clearance and localization of bleeding source are critical 5
- Do not miss biliary obstruction in liver abscess: Abscesses with biliary communication require endoscopic drainage in addition to antibiotics 8