Paroxysmal Nocturnal Hemoglobinuria (PNH)

A 38 year old male presents to the primary care physician with complaints of dark colored urine over the past few months. He also reports fatigue, generalized weakness, shortness of breath, and intermittent abdominal pain. He has a history of recurrent unexplained anemia requiring blood transfusions and a prior episode of deep venous thrombosis. On examination, he has pallor. Vital signs are stable. Laboratory studies show hemoglobin 8.0 g/dL, MCV 100 fL, reticulocytosis, markedly elevated LDH, elevated indirect bilirubin, and low haptoglobin. Direct antiglobulin test (Coombs test) is negative. Flow cytometry with FLAER demonstrates deficiency of GPI-anchored proteins, including CD55 and CD59. Diagnosis?

Diagnosis is Paroxysmal Nocturnal Hemoglobinuria (PNH).

1. Definition

Paroxysmal nocturnal hemoglobinuria is a rare acquired clonal hematopoietic stem cell disorder caused by a somatic mutation in the PIGA gene, resulting in deficiency of glycosylphosphatidylinositol (GPI)-anchored proteins and leading to complement-mediated intravascular hemolysis, thrombosis, and bone marrow failure.

2. Pathophysiology

1. Mutation in the X-linked PIGA gene impairs synthesis of the GPI anchor
2. Leads to absence of CD55 and CD59, which normally inhibit complement
3. Results in uncontrolled complement activation and chronic intravascular hemolysis
4. Free hemoglobin binds and depletes nitric oxide
5. Nitric oxide depletion causes smooth muscle dystonia, leading to abdominal pain, dysphagia, and erectile dysfunction
6. Complement activation, platelet activation, and impaired fibrinolysis contribute to thrombosis

3. Clinical Features

3.1 Hemolysis

1. Hemoglobinuria causing dark urine
2. Fatigue, pallor, and dyspnea
3. Coombs negative intravascular hemolytic anemia

3.2 Thrombosis

1. Venous thrombosis is most common
2. Occurs in unusual sites
3. Common sites include hepatic veins, portal veins, and cerebral veins

3.3 Bone Marrow Dysfunction

1. Cytopenias
2. Association with aplastic anemia or other marrow disorders

3.4 Other Features

1. Abdominal pain
2. Dysphagia or esophageal spasm
3. Renal impairment
4. Pulmonary hypertension
5. Erectile dysfunction

4. Laboratory Findings

1. Anemia
2. Reticulocytosis
3. Markedly elevated LDH
4. Unconjugated hyperbilirubinemia
5. Low haptoglobin
6. Negative Coombs test
7. Possible hemoglobinuria and hemosiderinuria
8. May show leukopenia or thrombocytopenia

5. Diagnosis

1. Flow cytometry with FLAER is the gold standard
2. Demonstrates deficiency of GPI-anchored proteins such as CD55 and CD59
3. Should evaluate erythrocytes, granulocytes, and monocytes
4. Older tests such as the Ham test and sucrose lysis test are obsolete

6. Complications

1. Thrombosis, the leading cause of death
2. Acute and chronic kidney disease
3. Bone marrow failure
4. Pulmonary hypertension
5. Progression to aplastic anemia or myelodysplastic syndrome

7. Management

7.1 Supportive Care

1. Blood transfusions
2. Folate and iron supplementation
3. Anticoagulation for thrombosis

7.2 Disease-Modifying Therapy

1. Eculizumab, a C5 inhibitor, reduces complement-mediated hemolysis
2. Ravulizumab, a longer-acting C5 inhibitor
3. Both increase susceptibility to Neisseria infections
4. Meningococcal vaccination is required prior to therapy

7.3 Curative Therapy

1. Allogeneic hematopoietic stem cell transplantation

8. Key Clinical Insight

Coombs negative intravascular hemolytic anemia + hemoglobinuria + thrombosis + absence of CD55/CD59 = PNH

9. Exam Level Pearls

1. Flow cytometry with FLAER is diagnostic
2. Thrombosis is the most serious complication and leading cause of death
3. Hepatic vein thrombosis is classic
4. Nitric oxide depletion explains smooth muscle symptoms
5. Eculizumab and ravulizumab are first-line therapies
6. Hemoglobinuria may not always be nocturnal
7. PNH can overlap with aplastic anemia

Sjögren Syndrome

A 38 year old female presents to her primary care physician with complaints of dry eyes and dry mouth for the past 6 months. She reports burning, itching, and a gritty sensation in both eyes and uses artificial tear drops frequently. She also has difficulty swallowing dry foods and needs to drink water frequently while eating. Examination reveals non-tender bilateral parotid gland enlargement. She has a history of rheumatoid arthritis diagnosed 2 years ago and is taking methotrexate once weekly with folinic acid. Vital signs are within normal limits. Serology shows positive ANA, rheumatoid factor, anti-SSA (Ro), and anti-SSB (La) antibodies. Schirmer test shows reduced tear production. Minor salivary gland biopsy demonstrates focal lymphocytic sialadenitis. Diagnosis?

Diagnosis is Secondary Sjögren syndrome.

1. Definition

Sjögren syndrome is a systemic autoimmune disease characterized by sicca symptoms, especially dry eyes and dry mouth, due to immune-mediated inflammation of the lacrimal and salivary glands. It may occur as primary or secondary disease.

2. Classification

1. Primary Sjögren syndrome occurs in isolation
2. Secondary Sjögren syndrome occurs with another autoimmune disease such as rheumatoid arthritis or systemic lupus erythematosus

3. Pathophysiology

1. Lymphocytic infiltration of exocrine glands
2. Characteristic lesion is focal lymphocytic sialadenitis
3. Leads to reduced tear and saliva production
4. B cell activation produces autoantibodies such as anti-SSA (Ro) and anti-SSB (La)
5. Chronic B cell activation increases risk of MALT lymphoma

4. Clinical Features

4.1 Glandular Features

1. Keratoconjunctivitis sicca causing dry, gritty eyes
2. Xerostomia causing dry mouth and difficulty swallowing
3. Parotid gland enlargement
4. Dental caries, tooth decay, and oral infections

4.2 Other Dryness

1. Vaginal dryness with dyspareunia
2. Dry skin
3. Dryness of the respiratory tract

4.3 Extraglandular Manifestations

1. Fatigue
2. Arthralgia or arthritis
3. Raynaud phenomenon
4. Cutaneous vasculitis
5. Interstitial lung disease
6. Renal involvement such as tubulointerstitial nephritis or renal tubular acidosis
7. Peripheral neuropathy or CNS involvement
8. Cryoglobulinemia and hypergammaglobulinemia

5. Diagnosis

5.1 Serology

1. ANA often positive but nonspecific
2. Rheumatoid factor may be positive
3. Anti-SSA (Ro) is the most diagnostically useful antibody
4. Anti-SSB (La) may also be present

5.2 Ocular Testing

1. Schirmer test ≤ 5 mm in 5 minutes indicates decreased tear production
2. Slit lamp examination with vital dye staining confirms keratoconjunctivitis sicca

5.3 Salivary Assessment

1. Unstimulated salivary flow ≤ 0.1 mL per minute is abnormal
2. Salivary gland ultrasonography is a useful noninvasive tool

5.4 Histopathology

1. Minor salivary gland biopsy is the most specific single test
2. Shows focal lymphocytic sialadenitis with focus score ≥ 1 per 4 mm²

6. Complications

1. Corneal damage and possible vision loss
2. Dental caries and tooth loss
3. Interstitial lung disease
4. Renal tubular acidosis
5. Peripheral neuropathy
6. Increased risk of B cell non-Hodgkin lymphoma, especially MALT lymphoma

7. Management

7.1 Dry Eyes

1. Preservative-free artificial tears
2. Nighttime lubricating gels or ointments
3. Topical cyclosporine or tacrolimus in selected cases
4. Punctal plugs for severe dryness

7.2 Dry Mouth

1. Frequent water intake
2. Sugar-free gum or lozenges
3. Saliva substitutes
4. Strict oral hygiene and regular dental care

7.3 Secretagogues

1. Pilocarpine
2. Cevimeline

7.4 Systemic Therapy

1. Not required for isolated sicca symptoms
2. Hydroxychloroquine, glucocorticoids, or immunosuppressive agents for extraglandular disease
3. Options include methotrexate, azathioprine, mycophenolate mofetil, or leflunomide
4. Rituximab may be used in severe cases

8. Key Clinical Insight

Dry eyes + dry mouth + parotid enlargement + anti-SSA positivity + focal lymphocytic sialadenitis = Sjögren syndrome

Association with rheumatoid arthritis confirms secondary Sjögren syndrome.

9. Exam Level Pearls

1. Anti-SSA (Ro) is the most useful antibody
2. Minor salivary gland biopsy is the most specific test
3. Schirmer test provides objective evidence of dry eyes
4. Up to 50 percent of patients develop extraglandular manifestations
5. Markedly increased risk of non-Hodgkin lymphoma
6. Persistent parotid enlargement, low C4, and cryoglobulinemia suggest higher lymphoma risk

Carcinoid Syndrome

A 55-year-old woman presents to the clinic with intermittent facial flushing, diarrhea, and wheezing for the past 6 months. She also reports crampy abdominal pain, nausea, and loose stools occurring 3 to 4 times daily, along with unintentional weight loss of 8 kg over 6 months. On examination, a holosystolic murmur at the left lower sternal border is heard on auscultation. Vital signs show blood pressure 120/80 mmHg, pulse 102/min, respiratory rate 18/min, oxygen saturation 92% on room air, and temperature 99.9°F. 24-hour urinary 5-HIAA is elevated. MRI of the abdomen and pelvis shows a small bowel mass with multiple liver metastases. Diagnosis?

Diagnosis is Carcinoid syndrome due to a metastatic small bowel neuroendocrine tumor.

1. Definition

Carcinoid syndrome is a clinical condition caused by systemic release of serotonin and other vasoactive substances from metastatic neuroendocrine tumors, most commonly after liver metastasis, leading to characteristic features such as flushing, diarrhea, and bronchospasm. It typically presents in the 5th to 7th decade.

2. Etiology

1. Midgut neuroendocrine tumors (most common), especially ileum or small intestine
2. Bronchial neuroendocrine tumors
3. Ovarian neuroendocrine tumors (can cause syndrome without liver metastasis)
4. Rarely pancreatic or other foregut tumors

3. Pathophysiology

1. Neuroendocrine tumors secrete serotonin, histamine, prostaglandins, and tachykinins
2. These substances are released into the portal circulation
3. The liver normally metabolizes them, preventing systemic effects
4. With liver metastasis, hepatic metabolism is bypassed
5. Circulating serotonin causes:
• Increased intestinal motility and secretion leading to diarrhea
• Vasodilation leading to flushing
• Bronchoconstriction leading to wheezing
6. Serotonin is metabolized to 5-HIAA, which is increased in urine
7. Tryptophan depletion leads to niacin deficiency (pellagra)

4. Clinical Features

4.1 Classic Features

1. Flushing (most common, episodic, triggered by stress, alcohol, or certain foods)
2. Watery diarrhea
3. Bronchospasm causing wheezing
4. Crampy abdominal pain

4.2 Cardiac Manifestations (Carcinoid Heart Disease)

1. Right-sided valvular lesions due to fibrotic plaques
2. Tricuspid regurgitation causing holosystolic murmur at LLSB
3. Pulmonic stenosis
4. May progress to right-sided heart failure
5. Left heart usually spared due to inactivation of serotonin in the lungs

4.3 Other Features

1. Weight loss and malnutrition
2. Malabsorption
3. Fatigue
4. Pellagra consisting of dermatitis, diarrhea, and dementia
5. Telangiectasia or persistent flushing
6. Mesenteric fibrosis leading to bowel obstruction or ischemia

5. Diagnosis

5.1 Biochemical Tests

1. 24-hour urinary 5-HIAA is the initial test of choice
2. Avoid serotonin-rich foods such as bananas, pineapples, walnuts, and avocados before testing
3. Chromogranin A is sensitive but nonspecific

5.2 Imaging

1. CT or MRI abdomen and pelvis for tumor localization
2. 68Ga-DOTATATE PET scan for highly sensitive detection
3. Somatostatin receptor scintigraphy as an alternative

5.3 Histology and Immunohistochemistry

1. Chromogranin A
2. Synaptophysin
3. Ki-67 index for tumor grading

5.4 Cardiac Evaluation

1. Echocardiography to assess valvular involvement

6. Management

6.1 First-line

1. Somatostatin analogs such as octreotide or lanreotide

6.2 Symptomatic Treatment

1. Avoid triggers such as alcohol, stress, and certain foods
2. Antidiarrheal agents such as loperamide
3. Correct dehydration and electrolyte imbalance
4. Niacin supplementation

6.3 Refractory Disease

1. Telotristat for persistent diarrhea
2. Peptide receptor radionuclide therapy (PRRT)
3. Targeted therapies such as mTOR inhibitors

6.4 Surgical

1. Tumor resection in localized disease
2. Debulking surgery in metastatic disease

6.5 Liver-directed Therapy

1. Hepatic artery embolization
2. Radioembolization
3. Ablation

7. Key Clinical Insight

Flushing + diarrhea + wheezing + elevated 5-HIAA + liver metastasis = carcinoid syndrome

8. Exam Level Pearls

1. Small bowel neuroendocrine tumor with liver metastasis is classic
2. Right-sided heart lesions are characteristic
3. 5-HIAA is the key diagnostic test
4. Somatostatin analogs are first line for symptom control
5. Niacin deficiency results from tryptophan diversion
6. Left-sided heart involvement suggests bronchial tumor or right-to-left shunt
7. Severe cases may develop carcinoid crisis triggered by surgery or stress